Total syntheses of pamamycin 607 and methyl nonactate: Stereoselective cyclisation of homoallylic alcohols that had been prepared with remote stereocontrol using allylstannanes

prepared with remote stereocontrol using functionalised

allylstannanes.⁷

Scheme 1 Direct cyclisation of homoallylic alcohols. Reagents and conditions:

(i) PhSeCl or PhSePhth, DCM, SnCl₄(20 mol%), r.t., 5 h (typically 50%); (ii)

Bu₃SnH, benzene, reﬂux, 2 h (85%).

Transmetallation of the (E)-5-benzyloxypent-2-enylstannane 3

using tin(^IV) chloride generates an allyltin trichloride that

reacts with aldehydes with excellent stereoselectivity in favour

of the 1,5-anti-(Z)-alk-3-enols 4.⁷Several procedures are known

for the stereoselective synthesis of 2,5-disubstituted tetrahydro-

furans from homoallylic alkenols^8–10and, as applied to the (Z)-

alkenols 4, were expected to provide access to the tetrahydro-

furans 5 which are reminiscent of those in the pamamycins

and methyl nonactate. In particular, they are characterised by

the presence of a methyl-bearing stereogenic centre next to the

2,5-cis-disubstituted tetrahydrofuran ring.

Scheme 2 Synthesis of (−)-methyl nonactate (2). Reagents and conditions: (i)

3, SnCl₄, −78 °C, 5 min, add 10, −78 °C, 45 min (82%, 4,8-anti : 4,8-syn > 96 : 4);

(ii) PhSePhth, DCM, SnCl₄(20 mol%), r.t., 20 h (62%); (iii) Bu₃SnH, benzene,

reﬂux, 2 h (85%); (iv) 10% Pd/C, H₂, EtOH, AcOH, r.t., 52 h (73%); (v) (a) PDC,

DMF, r.t., 24 h (82%), (b) Me₃SiCHN₂, hexane, benzene, MeOH, r.t., 30 min

(78%); (vi) TBAF, THF, r.t., 7 h (78%); (vii) MeOH, cH₂SO₄, reﬂux, 48 h (66%).

cyclisation with participation of the envelope conformation 9

in which the R′ group is in the less hindered pseudo equatorial

position.¹²However, this mechanism was not investigated and

it was not confirmed whether kinetic or thermodynamic

factors were controlling the stereoselectivity of product for-

mation under these conditions.

This procedure was applied to complete a synthesis of

(−)-methyl nonactate (2), see Scheme 2. The tin(^IV) chloride

mediated reaction between the stannane 3 and (S)-3-tert-butyl-

diphenylsilyloxybutanal (10)¹³gave the (Z)-4,8-anti-product 11

with useful stereoselectivity (4,8-anti : 4,8-syn > 96 : 4). This on

treatment with phenylselenenyl phthalimide and 20 mol%

tin(^IV) chloride cyclised to give the tetrahydrofuran 12. Desele-

nation was achieved using tributyltin hydride, tetrahydrofuran

13 being isolated essentially as a single stereoisomer (>95 : 5)

after chromatography. Hydrogenolysis gave the primary

alcohol 14 that was oxidised to the corresponding carboxylic

acid using pyridinium dichromate. Esterification using tri-

methylsilyl diazomethane then gave the ester 15 and desilyla-

tion with tetrabutylammonium fluoride gave (−)-methyl

nonactate (2).³The structure of (−)-methyl nonactate was con-

firmed by comparison with a racemic sample prepared from

nonactin using a known procedure, see Scheme 2.¹⁴

Results and discussion

Phenylselenenyl chloride or phthalimide induced cyclisation

of (Z)-homoallylic alcohols; synthesis of methyl nonactate (2)

Attempts to convert (Z)-alkenols 4 into tetrahydrofurans using

iodine in aqueous acetonitrile buﬀered with sodium hydrogen

carbonate,⁸were complicated by competing debenzylation and

gave complex mixtures of products. Initial studies using phe-

nylselenenyl chloride⁹were also slow and ineﬃcient. However,

it was found that cyclisation could be achieved using either

phenylselenenyl chloride or phthalimide in the presence of tin(^IV)

chloride (20 mol%). Using this procedure, the (Z)-non-6-en-

4-ol 6, prepared from butanal using the stannane 3,⁷gave the

tetrahydrofuran 7 that was reduced using tributyltin hydride

under free-radical conditions to give the 2,5-disubstituted

tetrahydrofuran 8, see Scheme 1. Tetrahydrofuran 8 was identi-

cal to a sample prepared earlier by a longer synthesis.¹¹

Synthesis of the C(1)–C(18) component of pamamycin 607

This cyclisation of alkenol 6 into the tetrahydrofuran 7 is This synthesis of (−)-methyl nonactate (2) shows how the phe-

consistent with reversible alkene phenylselenation followed by nylselenenyl induced cyclisation of homoallylic alcohols

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Fig. 1 Strategy for synthesis of the C(1)–C(18) fragment of pamamycin 607.

prepared using allylstannanes with (Z)-1,5-anti-stereocontrol

can be used to synthesize 2,5-cis-disubstituted tetrahydrofur-

ans reminiscent of those in pamamycin 607 (1). Pamamycin

607 is a macrodiolide and it was decided to prepare the two

constituent hydroxy-acids separately leaving the esterification

and macrocyclisation steps to the end of the synthesis. A linear

synthesis was envisaged for the more complex C(1)–C(18)

hydroxy-acid starting at the C(18) end, see Fig. 1. Retrosyntheti-

cally, the C(1)–C(18)-acid 16 was to be prepared from the alde-

Scheme 3 Synthesis of an amidoalkyl substituted tetrahydrofuran. Reagents

and conditions: (i) (R)-BnNCH(CH₃)Ph, ⁿBuLi, −78 °C, THF, −78 °C, 30 min, add

20, −78 °C, 2 h (89%); (ii) Pd(OH)₂/C, MeOH, ammonium formate, r.t., 15 min,

add 21, r.t., 1 h (91%); (iii) K₂CO₃, BnCO₂Cl, Et₂O, H₂O, 0 °C – r.t., 3 h (88%); (iv)

LiAlH₄, Et₂O, 0 °C – r.t., 2 h (80%); (v) (COCl)₂, DMSO, DCM, −78 °C, 5 min, add

alcohol 24, −78 °C, 20 min, add Et₃N, warm to r.t. (99%); (vi) 3, SnCl₄, −78 °C,

5 min, add 25, −78 °C, 50 min (64%); (vii) PhSeCl, SnCl₄, DCM, r.t., 15 h (25%);

(viii) Bu₃SnH, AIBN (cat.), toluene, reﬂux, 1 h (64%).

hyde 17 by reaction with allylstannane

3 followed by

phenylselenenyl induced cyclisation to form the second 2,5-

cis-disubstituted tetrahydrofuran ring. The aldehyde 17 should

be accessible by a Felkin–Anh controlled anti-selective aldol

reaction of the aldehyde 18 that in turn should be available

from the protected 3-aminohexanal 19 by reaction with allyl-

stannane 3, phenylselenenyl induced cyclisation and

deselenation.

The diastereoselective conjugate addition of chiral lithium

amides to α,β-unsaturated esters developed by Davies was used

to prepare the protected (R)-3-aminohexanal 25.¹⁵The conju-

gate addition of lithiated (R)-N-benzyl-α-methylbenzylamine to

tert-butyl (E)-hex-2-enoate (20)¹⁶gave the adduct 21 with excel-

lent stereoselectivity and transfer hydrogenolysis gave the

amino-ester 22 that was protected as its N-benzyloxycarbonyl

derivative 23. Reduction to the alcohol 24 and oxidation led to

aldehyde 25 and the tin(^IV) promoted reaction of this with stan-

nane 3 gave the (Z)-2,6-anti-alkenol 26 with good stereoselectiv-

ity. Cyclisation of the alkenol using phenylselenenyl chloride

in the presence of tin(^IV) chloride gave the tetrahydrofuran 27,

but only in a modest 25%, yield. Nevertheless, deselenation

using tributyltin hydride gave the 2,5-cis-disubstituted tetra-

hydrofuran 28, see Scheme 3.

Scheme 4 Synthesis of the C(8)–C(18) fragment of pamamycins. Reagents and

conditions: (i) TsCl, Et₃N, DCM, 0 °C – r.t., 24 h (95%); (ii) NaH, MeI, THF, r.t., 15 h

(99%); (iii) LiAlH₄, Et₂O, 0 °C, 1.5 h (96%); (iv) (COCl)₂, DMSO, DCM, −78 °C,

5 min, add alcohol 31, −78 °C, 20 min, Et₃N, r.t., 1.5 h (99%); (v) 3, SnCl₄, DCM,

−78 °C, 5 min, add 32, −78 °C, 50 min (64%); (vi) PhSeCl, SnCl₄, DCM, r.t., 20 h

(42%); (vii) Bu₃SnH, AIBN (cat.), benzene, reﬂux, 1.25 h (94%); (viii) 10% Pd/C,

EtOH, AcOH, H₂, r.t., 16 h (91%); (ix), (COCl)₂, DMSO, DCM, −78 °C, 5 min, add

alcohol 36, −78 °C, 20 min, Et₃N, r.t., 1.5 h (90%).

Configurations were assigned to the products 26–28 on the

basis of precedent and were consistent with spectroscopic tin(^IV) halide promoted reaction of aldehyde 32 with the stan-

data. However, the key cyclisation step was accompanied by nane 3 gave the required homoallylic alcohol 33 with excellent

the formation of several side-products that were not tetra- stereoselectivity. Although the cyclisation of the alcohol 33

hydrofurans and it appeared that the cbz-protected amine had induced by reaction with phenylselenenyl chloride–tin(^IV)

interfered with the cyclisation. It was therefore necessary to chloride still gave some non-tetrahydrofuran containing side-

study other amine derivatives to see if alternative protecting products, the yield of the tetrahydrofuran 34 was 42% after

groups could be found that were more compatible with the chromatography and this was deemed acceptable at this stage

tetrahydrofuran formation.

of the project. Reduction using tributyltin hydride gave the

N-Tosylation of the amino-ester 22 gave the sulfonamide 29 2,5-cis-disubstituted tetrahydrofuran 35. This was hydrogeno-

that was methylated on nitrogen to introduce the first of the lysed to give the alcohol 36 that was oxidised to complete a

two N-methyl groups present in the pamamycins. The resulting synthesis of the aldehyde 37, see Scheme 4. Aldehyde 37

N-methylsulfonamide 30 was then converted into the aldehyde corresponds to the aldehyde 18 in the proposed strategy for a

32, by reduction to alcohol 31 followed by oxidation, and the synthesis of pamamycin 607 (see Fig. 1).

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The next stage in the synthesis was to carry out a Felkin–

Anh controlled anti-aldol condensation of aldehyde 37 to

prepare a compound with the correct configurations at C(2)

and C(3) for incorporation into a pamamycin, cf. 17 in Fig. 1.

To minimise the use of chiral reagents, it was decided to

employ the lithium enolate derived from 2,6-dimethylphenyl

propanoate (61).¹⁹

In the event, the reaction of the lithium enolate of the aryl

ester 61 with aldehyde 37 gave three products in a ratio of

19 : 72 : 9 that were identified as the anti,anti-, the anti,syn- and

the syn,syn-products 46, 48 and 50, respectively. The most

polar product was the syn,syn-isomer 50 that could be separ-

ated from a mixture of the less polar products 46 and 48. The

two 2,3-anti-products 46 and 48 could not be separated but

after silylation of the mixture, the tert-butyldimethyl silyl

ethers 47 and 49 could be separated. The syn,syn-isomer 50

was also converted into its tert-butyldimethyl silyl ether 51 for

comparison, see Scheme 6.

Scheme 5 Correlation of the tetrahydrofuran 35 with the known ester 45.

Reagents and conditions: (i) Na, naphthalene, DME, sonicated, r.t., 12 min,

added to 35 in DME, −60 °C, 1 h (85%); (ii) (^tBuOCO)₂O, Et₃N, THF, r.t., 16 h

(90%); (iii) 10% Pd/C, EtOH, H₂, r.t., 16 h (89%); (iv) Dess–Martin periodinane,

DCM, r.t., 40 min (ca. 100%); (v) NaClO₂, ^tBuOH, H₂O, 2-methylbut-2-ene,

NaH₂PO₄, r.t., 2 h; (vi) Me₃SiCHN₂, benzene, MeOH, r.t., 1.5 h (75% from the

aldehyde); (vii) cHCl, EtOAc, r.t., 15 h (48%); (viii) formalin, MeCN, NaBH₃CN, r.t.,

1 h (52%).

To confirm the structure of the major silyl ether 49, it was

reduced to the alcohol 52. This was desilylated to give the diol

53 and treatment of this with carbonyl di-imidazole gave the

cyclic carbonate 54. Authentic samples of the cyclic carbonate

54 and its anti,anti-diastereoisomer 60, were prepared from the

starting aldehyde 37 via the ester 55 synthesized by an (E)-

selective Wittig reaction using methoxycarbonylmethylene tri-

phenylphosphorane. Reduction of ester 55 gave the allylic

alcohol 56 and epoxidation of this alcohol under Sharpless

conditions gave epoxide 57 using (+)-diethyl tartrate and

epoxide 58 using (−)-diethyl tartrate, with excellent stereoselec-

tivities in both cases, the configurations of these epoxides

being assigned by the Sharpless mnemonic.²⁰Ring-opening

the epoxide 57 using a methyl cuprate gave the diol 53 and

hence the carbonate 54 that had been prepared from the

Although the structure of the tetrahydrofuran 35 was con-

sistent with the earlier work and with its spectroscopic data, it

was decided to confirm its structure by correlation with a

known compound. Thus sodium naphthalenide was used to

reduce the tosylamide 35 to the amine 38 and this was acylated

to prepare its N-Boc derivative 39. Hydrogenolysis gave the

alcohol 40 and oxidation via the aldehyde 41 provided the

ester 43 after reaction of the intermediate acid 42 with tri-

methylsilyl diazomethane. Following removal of the Boc-group

under acidic conditions,¹⁷reductive methylation of the result-

ing secondary amine 44 using formalin and sodium

cyanoborohydride¹⁸gave the dimethylamino-ester 45, see

Scheme 5. This had spectroscopic data in good agreement

with those reported in the literature.^5k

Scheme 6 The anti-aldol condensation and conﬁrmation of the structures of the products. Reagents and conditions: (i) Pr₂NH, ⁿBuLi, THF, 0 °C, 15 min, cool to

−78 °C, add 61, −78 °C, 1 h, add 37, −78 °C, 1 h (46 + 48, 63%, 46 : 48 = 20 : 80; 50, 7%); (ii) 2,6-lutidine, TBSOTf, DCM, r.t., 15 h (47, 17%; 49, 66%, from 46 + 48;

51, 70% from 50); (iii) DIBAL-H, DCM, −78 °C, 30 min, warm to r.t., 1 h (80%); (iv) TBAF, THF, r.t., 2 h (89%); (v) CO(imid)₂, benzene, reﬂux, 15 h (54, 87%; 60, 67%);

(vi) Ph₃PCHCO₂Me, DCM, r.t., 48 h (81%); (vii) DIBAL-H, DCM, hexane, −78 °C, 30 min, warmed to r.t., 90 min (74%); (viii) (+)-DET (for 57), (−)-DET (for 58), DCM,

Ti(OiPr)₄, −23 °C, BuOOH, toluene, −23 °C, 2 h (57, 70%, 57 : 58 = 95 : 5; 58, 80%, 58 : 57 = 98 : 2); (ix) CuI, Et₂O, MeLi, −10 °C, 30 min, add epoxide, −10 °C, 5 h

(53, 57%; 59, 72%); (x) (a) DIBAL-H, DCM, −78 °C, 30 min, warm to r.t., 1.5 h (38%) (b) TBAF, THF, r.t., 2 h (70%).

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Scheme 7 Completion of the C(10)–C(18) fragment. Reagents and conditions: (i) (COCl)₂, DMSO, DCM, −78 °C, 5 min, add 52, −78 °C, 20 min, Et₃N, r.t., 1.5 h

(95%); (ii) 3, SnCl₄, DCM, −78 °C, 5 min, add 62, −78 °C, 50 min (83%); (iii) ZnCl₂, PhSePhth, r.t., 2 h (54%); (iv) Bu₃SnH, AIBN (cat.), benzene, reﬂux, 1.25 h (ca.

85%); (v) Na, naphthalene, DME, sonicated, r.t., 12 min, added to 65 in DME, −60 °C, 1 h (83%); (vi) (^tBuOCO)₂O, Et₃N, THF, r.t., 16 h (95%); (vii) 10% Pd/C, EtOH,

H₂, r.t., 16 h (82%); (viii) Dess–Martin periodinane, DCM, r.t., 40 min (ca. 100%); (ix) NaClO₂, ^tBuOH, H₂O, 2-methylbut-2-ene, NaH₂PO₄, r.t., 2 h (90%); (x)

Me₃SiCHN₂, benzene, MeOH, r.t. (73% from 69); (xi) cHCl, EtOH, r.t., 16 h (50%); (xii) formalin, NaCNBH₃, MeCN, r.t., 1 h, AcOH, r.t., 16 h (48%).

major aldol product 48. The diastereoisomeric epoxide 58 gave be isolated. The 2,5-cis-configuration of the newly formed

the diol 59 on treatment with the methyl cuprate and hence tetrahydrofuran ring was consistent with nOe studies.

the carbonate 60. The diol 59 was also prepared from the Reduction using tributyltin hydride then removed the phenyl-

minor aldol product 46 by reduction of the corresponding silyl selenenyl group to give the tetrahydrofuran 65, see Scheme 7.

ether 47 and desilylation. The diols 53 and 59, and the carbon-

At this point, the toluene 4-sulfonyl group had completed

ates 54 and 60, had distinctly diﬀerent ¹H and ¹³C NMR its task of preventing interference by the N-substituent in the

spectra that were consistent with the assigned structures, e.g. phenylselenenyl induced cyclisations. As its reductive removal

with H(2) and H(3) showing diaxial coupling in both cases, see would be incompatible with ester functionalities in later inter-

Scheme 6.

mediates, it was removed using sodium naphthalenide to give

This correlation confirmed the configuration assigned to the free secondary amine 66. This was protected as its tert-

the major aldol product 48 as the required 2,3-anti-3,4-syn-dia- butyloxycarbonyl derivative 67 and hydrogenolysis delivered

stereoisomer formed by an anti-selective aldol reaction under the primary alcohol 68. Oxidation via aldehyde 69 then gave

Felkin–Anh²¹control. The structure of the minor 2,3-anti-3,4- the carboxylic acid 70 that corresponds to the intact C(1)–C(18)

anti-isomer 46 followed from its correlation with the diol 59. component of pamamycin 607 and is ready for incorporation

The second minor product had to be a 2,3-syn-isomer and its into a final assembly of the natural product.

3,4-syn-configuration was assigned on the basis of Felkin–Anh

Structures were assigned to the intermediates in this

control. It was now necessary to develop the chemistry of the scheme on the basis of the earlier work and were consistent

alcohol 52 prepared from the major aldol product 48 to com- with spectroscopic data. The acid 70 was also converted into

plete a synthesis of the C(1)–C(18) component of pamamycin the known methyl ester 73 with the dimethylamino substitu-

607, see Scheme 7.

ent at C(15), by esterification using trimethylsilyl diazo-

Oxidation of the alcohol 52 using Swern conditions gave methane to give the ester 71 that was treated with acid to

the aldehyde 62. The tin(^IV) chloride promoted reaction of this remove the tert-butoxycarbonyl and tert-butyldimethylsilyl

aldehyde with the stannane 3 was again highly stereoselective groups and reductive methylation of the resulting monomethyl-

and gave the required (Z)-2,6-anti-product 63 with no evidence amine 72. The methyl ester 73 had physical and spectroscopic

of any other diastereoisomer (¹H, ¹³C NMR). The next step was properties consistent with those in the literature.^5l

the crucial cyclisation of this alcohol to give the required 2,5-

Synthesis of the C(1′)–C(11′) component of pamamycin 607

cis-disubstituted tetrahydrofuran, but this was regarded as a

stern test of the methodology since this substrate was more

hindered than the earlier substrates had been. In the event the

best results were obtained using phenylselenenyl phthalimide

with anhydrous zinc chloride as the Lewis acid. Under these

conditions the bis-tetrahydrofuran 64 was obtained in an

acceptable yield (54%) as the only diastereoisomer that could

The C(1′)–C(11′) fragment of pamamycin 607 contains a 2,5-

cis-disubstituted tetrahydrofuran with an α-methyl bearing

side-chain at C(2), but the configuration of the methyl bearing

stereogenic centre relative to the stereogenic centres in the

tetrahydrofuran is the opposite of that in the C(1)–C(18) com-

ponent. This necessitated an inversion step in the synthesis.

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Scheme 8 Synthesis of the C(1’)–C(11’) fragment of pamamycin 607. Reagents and conditions: (i) TBDPSCl, imid., DCM, r.t., 16 h (92%); (ii) DIBAL-H, THF, −78 °C,

1 h, then r.t., 1 h (94%); (iii) I₂, Ph₃P, imid., THF, r.t., 2 h (97%); (iv) 1,3-dithiane, ⁿBuLi, hexanes, THF, −20 °C, 1.5 h, added to 77, THF, 0 °C, 16 h (88%); (v) HgO, THF,

H₂O, r.t., BF₃·Et₂O 45 min (98%); (vi) (R)-3, SnCl₄, DCM, −78 °C, 5 min, add 79, −78 °C, 50 min (90%); (vii) 4-NO₂C₆H₄CO₂H, Ph₃P, Et₂O, toluene, DEAD, r.t., 2 h (81,

70%; diene 12%); (viii) NaOH, MeOH, r.t., 2 h (94%); (ix) PhSePhth, SnCl₄, DCM, r.t., 40 min (81%); (x) Bu₃SnH, AIBN (cat.), benzene, reﬂux, 2.5 h (99%); (xi) 10% Pd/

C, EtOH, AcOH, H₂, r.t., 15 h (89%); (xii) Dess–Martin periodinane, DCM, r.t., 1 h; (xiii) NaClO₂, ^tBuOH, H₂O, 2-methylbut-2-ene, NaH₂PO₄, r.t., 2 h; (xiv) BnBr, Pr₂NEt,

MeCN, r.t., 15 h (76% from 85); (xv) TFA, H₂O, r.t., 40 min (94%); (xvi) cHCl, MeOH, reﬂux, 2.5 h (99%); (xvii) 4-BrC₆H₄COCl, Et₃N, DMAP (cat.), DCM, r.t., 16 h (43%).

(S)-3-tert-Butyldiphenylsilyloxyhexanal (79) was prepared Completion of a synthesis of pamamycin 607

from the known methyl (S)-2-hydroxypentanoate (74)²²by

Fortuitously, it was decided to join the C(1)–C(18) and C(1′)–

reduction of the corresponding silyl ether 75 using DIBAL-H to

C(11′) fragments by formation of the ester using the acid 70 of

give the alcohol 76. This was converted into the iodide 77 that

the C(1)–C(18)-component and the alcohol 89 of the C(1′)–

was used to alkylate 1,3-dithiane to prepare the 2-alkyldithiane

C(11′) component.²⁴Esterification of acid 70 using the alcohol

78. Hydrolysis of this gave the required aldehyde 79.

The tin(^IV) chloride promoted reaction of the (R)-stannane

(R)-3 with the (S)-3-tert-butyldiphenylsilyloxyhexanal (79) gave

89 under Yamaguchi conditions²⁵gave the ester 92. Desilyla-

tion using tetrabutylammonium fluoride was complicated by

base promoted tetrahydrofuran ring-opening and so had to be

carried out under acidic conditions that led to loss of the tert-

butoxycarbonyl group. This was reinstated to give the hydroxy-

the homoallylic alcohol 80 with excellent stereoselectivity, just

ca. 5% of the 1,5-syn-epimer being detected by ¹³C NMR. At

this point the configuration at C(6) had to be inverted. Treat-

ester 93 that was hydrogenolysed to give the seco-acid 94.

ment of the alcohol 80 with 4-nitrobenzoic acid under Mitsu-

Macrocyclisation was then achieved in a modest, albeit unopti-

nobu conditions²³gave the ester 81 with the desired inversion

mised, yield using the modified Yamaguchi conditions²⁵to

of configuration and 12% of a side-product provisionally ident-

ified as (2S,8S,3Z,5EZ)-1-benzyloxy-8-tert-butyldiphenylsilyloxy-

2-methylundeca-3,5-diene. Saponification of the ester 81 gave

the alcohol 82 that was cyclised using phenylselenenyl phthali-

mide and tin(^IV) chloride to give the tetrahydrofuran 83. Reduc-

tive removal of the phenylselenenyl group using tributyltin

hydride then gave the 2,5-cis-disubstituted tetrahydrofuran 84.

This was debenzylated to give the primary alcohol 85 and oxi-

give the macrodiolide 95. It remained to remove the tert-

butoxycarbonyl group and to methylate the resulting second-

ary amine to complete a synthesis of a pamamycin. This was

carried out using the conditions that had been used for the

conversion of the monotetrahydrofuran 43 into the dimethyl-

amine derivative 45, see Scheme 5, namely acid catalysed

removal of the Boc-group to give pamamycin 593 (96), which

itself is a natural product,^1dfollowed by reductive methylation

dation via the aldehyde 86 gave the acid 87. O-Alkylation using

benzyl bromide under basic conditions gave the benzyl ester

88 and desilylation using trifluoroacetic acid provided the

using formalin and sodium cyanoborohydride.¹⁸This gave

pamamycin 607 (1) that was compared directly with a sample

of the natural material. The trifluoroacetate salts of the syn-

hydroxy ester 89 ready for incorporation into a pamamycin, see

thetic and natural pamamycin 607 (1)^1awere shown to be iden-

Scheme 8.

tical by ¹H and ¹³C NMR spectroscopy (Scheme 9).

The structures of the compounds in this scheme were

assigned by analogy with the earlier work. However, the tetra-

hydrofuran 83 contained a minor inseparable impurity, ca.

20%, that may have been a diastereoisomer of the major

Summary and conclusions

product, but this was not confirmed. It was removed during

chromatography of the tetrahydrofurans 83 and 84. The struc-

ture assigned to the tetrahydrofuran 85 was confirmed by de-

silylation to the known diol 90^1cthat was bis-acylated to give

the known 4-bromobenzoate 91 (Scheme 8).^5j

This synthesis of pamamycin 607 (1) features the use of

remote stereocontrol using allylstannanes and the stereo-

selective Lewis acid promoted cyclisation of (Z)-homoallylic

alcohols using phenylselenenyl electrophiles, both of these

reactions being used successfully with complex chiral

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Scheme 9 Completion of a synthesis of pamamycin 607 (1). Reagents and conditions: (i) DMAP, 2,4,6-trichlorobenzoyl chloride, DCM, r.t., 3.5 h (78%); (ii) (a) cHCl,

EtOH, 55 °C, 3.5 h (b) (^tBuOCO)₂O, Et₃N, DCM, r.t., 16 h (93%); (iii) 10% Pd/C, EtOH, H₂, r.t., 16 h (97%); (iv) Et₃N, 2,4,6-trichlorobenzoyl chloride, xylene, r.t., 14 h,

add DMAP, r.t., 24 h (25%); (v) (a) TFA, DCM, r.t., 45 min (82%) (b) formalin, NaBH₃CN, MeCN, r.t., 1.5 h, then AcOH, r.t. 21 h (70%).

substrates. In this synthesis, all the stereogenic centres, apart

from those at C(15) and at C(8′) were derived from the allyl-

stannanes or were induced from centres formed during allyl-

Experimental

General experimental procedures

stannane reactions. Indeed, the only chiral starting materials ¹H and ¹³C NMR spectra were recorded on Varian Unity 500,

used in this synthesis were the (R)- and (S)-4-methylpent-2- Varian Unity Inova 400 and Varian Unity Inova 300 spec-

enylstannanes (R)- and (S)-3, the ester 74 and (R)-N-benzyl- trometers with residual non-deuterated solvent as the internal

α-methylbenzylamine.

standard. IR spectra were recorded on an ATI Mattson Genesis

The synthesis of the C(1)–C(18)-component is a linear syn- FTIR as thin films produced by evaporation of a DCM solution

thesis and perhaps convergent alternatives could be envisaged, on sodium chloride plates unless otherwise stated. Mass

but the use of the Felkin–Anh controlled anti-selective aldol spectra were recorded on Micromass VG Trio 200 and Kratos

reaction to introduce the required stereogenic centres at C(7) Concept IS spectrometers. Chemical ionisation (CI) was per-

and C(8) directly did provide a concise assembly strategy. In formed using ammonia. Typical clusters of isotope peaks were

this step it would have been possible to use a chiral aldol observed for bromine-, selenium- and tin-containing com-

reagent for improved stereoselectivity, but the aldol reaction pounds. Only those corresponding to ⁷⁹Br, ⁸⁰Se and ¹²⁰Sn are

using the ester 61 made use of the chirality embedded in the reported. Chromatography refers to flash column chromato-

substrate to control its stereoselectivity, in line with the philo- graphy using Merck silica gel 60H (40–60 nm,

sophy of the synthesis.

26 230–300 mesh).

In this work, some of the earlier steps involving the pent-2-

Tetrahydrofuran (THF) was dried and distilled from sodium

enylstannanes (R)- and (S)-3 were carried out successfully metal using benzophenone as an indicator under an atmos-

on multigramme scales on quite complex substrates, yet phere of nitrogen. DCM (DCM) was dried and distilled from

the remote stereocontrol introduced by the stannane calcium hydride under an atmosphere of nitrogen. Ether refers

dominated over any intrinsic stereochemical preference of to diethyl ether, which was dried and distilled from sodium

the starting material. Moreover, the use of organotin metal using benzophenone as an indicator under an atmos-

reagents could be avoided by using the analogous organo- phere of nitrogen. Light petroleum refers to the fraction of

germanium compounds that have been introduced more light petroleum ether distilled between 40–60 °C. Benzene and

recently and which tend to react with even better hexane were dried over sodium metal. Butyllithium (1.6 M in

stereoselectivity.²⁶

hexanes) was titrated against a solution of propan-2-ol in

The use of a Lewis acid to promote the phenylselenenyl xylene with 2,2′-bipyridine as an indicator. Triethylamine and

induced cyclisations of the (Z)-homoallylic alcohols to give 2,5- diisopropylamine were dried over potassium hydroxide pellets.

cis-disubstituted tetrahydrofurans was not optimised.²⁷Brine refers to saturated aqueous sodium chloride. Zinc(^II)

However, the beneficial eﬀect of having a Lewis acid present chloride was dried in Kugelrohr at 220 °C for 7 h at high

was observed for both phenylselenenyl chloride and phthali- vacuum, allowed to cool to 50 °C at the same pressure and

mide induced cyclisations. Tin(^IV) chloride was usually used as then allowed to cool to room temperature in desiccator.

the Lewis acid although the use of zinc chloride gave a

tert-Butyl (E)-hex-2-enoate (20)¹⁶was prepared as colourless

better yield in a later example. However, studies to establish liquid from butanal using tert-butoxycarbonylmethylene-(tri-

which Lewis acid–phenylselenenyl reagent combination was phenyl)phosphorane (Found: M⁺+ NH₄, 188.1648. C₁₀H₂₂NO₂

the optimum for a broad range of substrates, were not requires M, 188.1650); δ_H(CDCl₃, 300 MHz) 0.98 (3 H, t, J 7.4,

undertaken.

6-H₃), 1.52 [9 H, s, C(CH₃)₃], 1.45–1.60 (2 H, m, 5-H₂), 2.19

This journal is © The Royal Society of Chemistry 2012

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(2 H, dq, J 0.5, 7.3, 4-H₂), 5.78 (1 H, d, J 15.5, 2-H) and 6.90 (1 2.14 (each 1 H, m, 5-H), 2.74 (1 H, m, 8-H), 3.20 (2 H, m, 9-H₂),

H, dt, J 15.5 and 6.9, 3-H); δ_C(CDCl₃, 75 MHz) 13.6, 21.3, 28.1, 3.23 (1 H, m, OH), 3.85 (1 H, m, 4-H), 4.05 (1 H, m, 2-H), 4.42

34.0, 79.9, 123.0 and 147.8; m/z (CI) 188 (M⁺+ 18, 100%), 171 (2 H, s, PhCH₂), 5.21 (1 H, t, J 10, 7-H), 5.35 (1 H, m, 6-H),

(M⁺+ 1, 90) and 132 (80).

7.06–7.40 (11 H, m, ArH) and 7.56–7.68 (4 H, m, ArH); δ_C

(2S,3S,4S,6R)-1-B^ENZYLOXY-3,6-EPOXY-2-METHYL-4-PHENYLSELENONONANE (CDCl₃, 75 MHz) 17.5, 19.1, 23.0, 26.9, 32.3, 35.9, 44.9, 67.9,

(7). Phenylselenenyl chloride (112 mg, 0.58 mmol) and SnCl₄68.4, 72.9, 74.9, 126.0, 127.4, 127.5, 128.2, 129.5, 129.6, 135.2

(1 M in DCM, 80 μL, 0.08 mmol) were added slowly to the and 135.8; m/z (CI) 534 (M⁺+ 18, 23%) and 517 (M⁺+ 1, 100).

alkenol 6 (102 mg, 0.39 mmol) in DCM (2 mL) and the mixture

(2S,3S,4S,6R,8S)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-

stirred for 5 h. Aqueous sodium bicarbonate was added and 2-^METHYL-4-PHENYLSELENONONANE

(12). N-Phenylselenophthali-

the aqueous layer extracted with DCM. The organic extracts mide (1.7 g, 5.5 mmol) and tin(^IV) chloride (0.74 mL, 1.0 M in

were dried (MgSO₄) and concentrated under reduced pressure. DCM, 0.74 mmol) were added to the alcohol 11 (1.9 g,

Chromatography of the residue using 10 : 1 light petroleum : 3.7 mmol) in DCM (20 mL) at room temperature and the sol-

ether gave the title compound 7 (81 mg, 50%) as a colourless oil ution stirred for 20 h. Saturated aqueous sodium bicarbonate

(Found: M⁺, 418.1417. C₂₃H₃₀O₂⁸⁰Se requires M, 418.1411); (30 mL) was added and the aqueous phase extracted with DCM

ν_max/cm⁻¹3061, 3029, 1579, 1476, 1453, 1372, 1103, 1073, (3 × 15 mL). The organic extracts were washed with water

1024, 735 and 694; δ_H(CDCl₃, 300 MHz) 0.97 (3 H, t, J 7.2, 9- (20 mL) and brine (20 mL), dried (MgSO₄) and concentrated

H₃), 1.1 (3 H, d, J 6.7, 2-CH₃), 1.20–1.6 (3 H, m), 1.78 (1 H, m), under reduced pressure. Chromatography of the residue using

1.98 (1 H, ddd, J 13.8, 5.7 and 2.1, 5-H), 2.24 (1 H, m, 2-H), 20 : 1 light petroleum : ether (20 : 1) gave the title compound 12

2.63 (1 H, m, 5-H′), 3.58 (1 H, dd, J 9 and 6.9, 1-H), 3.65 (1 H, (1.5 g, 62%) as a colourless oil, [α]²_D¹+27 (c 1.8 in DCM)

dd, J 9.6 and 4.2, 3-H), 3.74 (1 H, dd, J 9 and 3.3, 1-H′), 3.84 (Found: M⁺, 672.2541. C₃₉H₄₈O₃SiSe requires M, 672.2538); δ_H

and 3.92 (each 1 H, m), 4.55 and 4.64 (each 1 H, d, J 12.2, (CDCl₃, 300 MHz) 0.95 [15 H, m, SiC(CH₃)₃, 9-H₃and 2-CH₃),

PhHCHO) and 7.36–7.6 (10 H, m, ArH); δ_C(CDCl₃, 75 MHz) 1.74 (3 H, m, 5-H and 7-H₂), 2.10 (1 H, m, 2-H), 2.45 (1 H, m,

14.1, 14.5, 19.6, 37.1, 38.6, 40.3, 46.3, 72.9, 73.0, 78.1, 83.8, 5-H′), 3.36 (1 H, dd, J 7 and 9, 4-H), 3.41 (1 H, dd, J 4 and 9, 1-

127.1, 127.2, 127.4, 128.2, 129.0, 130.2, 133.9 and 138.9; m/z H), 3.61 (1 H, dd, J 3 and 9, 1-H′), 3.68 (1 H, m, 6-H), 4.00 (2 H,

(EI) 418 (M⁺, 2%) and 91 (100).

m, 3-H and 8-H), 4.41 and 4.46 (each 1 H, d, J 12, PhHCH),

(2S,3R,6R)-1-B^ENZYLOXY-3,6-EPOXY-2-METHYLNONANE (8).¹¹Tribu- 7.16–7.37 (14 H, m, ArH), 7.42 (2 H, m, ArH) and 7.56–7.65 (4

tyltin hydride (70 μL, 0.264 mmol) was added to the phenylse- H, m, ArH); δ_C(CDCl₃, 75 MHz) 14.4, 19.3, 24.2, 27.0, 37.0,

lenide 7 (55 mg, 0.132 mmol) in thoroughly degassed benzene 40.7, 46.2, 46.7, 67.6, 73.0, 73.1, 74.9, 83.9, 127.1, 127.3, 127.4,

(10 mL) and the solution heated under reflux for 2 h. After con- 128.2, 129.0, 129.3, 129.4, 130.1, 133,9, 134.3, 134.9, 135.8 and

centration under reduced pressure, chromatography of the 138.9; m/z (CI) 690 (M⁺+ 18, 100%) and 673 (M⁺+ 1, 30).

residue using 10 : 1 light petroleum : ether gave the title com-

(2S,3R,6S,8S)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-

pound 8¹¹(29 mg, 85%) as a colourless oil (Found: M⁺+ H, 2-^METHYLNONANE(13). The tetrahydrofuran 12 (1.4 g, 2.2 mmol),

263.2016. C₁₇H₂₇O₂requires M, 263.2011); δ_H(CDCl₃300 MHz) tributyltin hydride (1.2 mL, 4.4 mmol) and azobis-isobutyroni-

0.98 (6 H, m, 2-CH₃and 9-H₃), 1.32–1.66 (7 H, m), 1.92 (2 H, trile (cat.) in benzene (25 mL) was degassed for 45 min and

m), 3.4 (1 H, dd, J 9 and 7.4, 1-H), 3.65 (1 H, dd, J 9 and 4.6, then heated under reflux for 2 h. After concentration under

1-H′), 3.73 (1 H, q, J 7.4, 3-H), 3.84 (1 H, m, 6-H), 4.55 (2 H, s, reduced pressure the residue was chromatographed 15 : 1 light

PhCH₂) and 7.37 (5 H, m, ArH); δ_C(CDCl₃, 75 MHz) 13.5, 14.2, petroleum : ether to give the title compound 13 (0.96 g, 85%) as

19.3, 28.4, 30.9, 38.2, 38.9, 72.9, 73.2, 78.9, 80.5, 127.2, 127.4, a colourless oil, [α]²_D¹−8.8 (c 0.9 in DCM) (Found: M⁺,

128.2 and 138.8; m/z (CI) 263 (M⁺+ 1, 100).

516.3063. C₃₃H₄₄O₃Si requires M, 516.3060); ν_max/cm⁻¹3069,

(2S,4S,8R,6Z)-9-B^ENZYLOXY-2-TERT-BUTYLDIPHENYLSILYLOXY-8-METHYL- 3047, 1454, 1427, 1375, 1109, 1074, 821, 736 and 702; δ_H

^NON-6-EN-4-OL (11). Tin(IV) chloride (0.18 mL, 1.0 M in DCM, (CDCl₃, 300 MHz) 0.96 (3 H, d, J 6, 2-CH₃), 1.09 [12 H, m, SiC-

0.18 mmol) cooled to −78 °C was added to the stannane 3 (CH₃)₃and 9-H₃], 1.15–1.98 (7 H, m, 4-H₂, 5-H₂, 7-H₂and 2-H),

(90 mg, 0.18 mmol) in DCM at −78 °C. After 5 min, the alde- 3.36 (1 H, dd, J 7 and 9, 1-H), 3.61 (2 H, m, 3-H and 1-H′), 3.90

hyde 10¹³(76 mg, 0.22 mmol) in DCM (1.5 mL) cooled at (1 H, m, 6-H), 4.08 (1 H, m, 8-H), 4.54 (2 H, s, PhCH₂),

−78 °C was added and the solution was stirred for 45 min at 7.36–7.48 (11 H, m, ArH) and 7.72–7.78 (4 H, m, ArH); δ_C

−78 °C. Saturated aqueous sodium bicarbonate (7 mL) was (CDCl₃, 75 MHz) 13.7, 19.3, 24.13, 27.0, 28.6, 31.2, 39.0, 46.2,

added and the aqueous phase was extracted with DCM (3 × 67.8, 72.9, 73.3, 75.8, 80.6, 127.3, 127.4(2), 128.2, 129.3(2),

5 mL). The organic extracts were washed with water (20 mL) 134.3, 135.0, 135.7, 135.8, 135.9 and 138.8; m/z (CI) 534 (M⁺+

and brine (20 mL), dried (MgSO₄) and concentrated under 18, 35%), 517 (M⁺+ 1, 12) and 439 (100).

reduced pressure. Chromatography of the residue 4 : 1 light

(2S,3R,6S,8S)-8-^TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-2-METHYLNO-

petroleum : ether gave the title compound 11 (80 mg, 82%) as a ^NAN-1-OL (14). Palladium (0.03 g, 10% on carbon) was added to

colourless oil, [α]²_D¹−1.9 (c 1.7 in DCM) (Found: M⁺+ H, the benzyl ether 13 (0.23 g, 0.43 mmol) in ethanol (20 mL) and

517.3123. C₃₃H₄₅O₃Si requires M, 517.3138); ν_max/cm⁻¹3429, acetic acid (0.2 mL) at room temperature and the suspension

1643, 1428, 1110 and 702; δ_H(CDCl₃, 300 MHz) 0.87 (3 H, d, J stirred under an atmosphere of hydrogen for 52 h. The mixture

6, 8-CH₃), 0.96 [12 H, m, SiC(CH₃)₃and 1-H₃), 1.45 (1 H, ddd, J was filtered through Celite® and the solid residue was washed

3, 6 and 14, 3-H), 1.56 (1 H, ddd, J 4, 9 and 14, 3-H′), 2.08 and with ethanol (2 × 20 mL). The filtrate was concentrated under

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Organic & Biomolecular Chemistry

reduced pressure and the residue chromatographed 4 : 1 light −15.6 (c 1.4 in DCM), enantiomer lit.^3a[α]_D²¹+19.1 (c 0.45 in

petroleum : ether to give the title compound 14 (0.14 g, 73%) as CHCl₃) (Found: M⁺, 216.1359. C₁₁H₂₀O₄requires M, 216.1362);

a colourless oil, [α]²_D¹+17.8 (c 1.8 in DCM) (Found: M⁺, ν_max/cm⁻¹3421, 1736, 1461, 1374, 1266, 1201, 1163, 1089 and

427.2665. C₂₆H₃₈O₃Si requires M, 427.2668); ν_max/cm⁻¹3323, 1060; δ_H(CDCl₃, 300 MHz) 1.06 (3 H, d, J 8, 2-CH₃), 1.14 (3 H,

1427, 1110, 821, 794, 739 and 703; δ_H(CDCl₃, 300 MHz) 0.72 (3 d, J 6, 9-H₃), 1.52–1.64 (3 H, m, 5-H₂and 7-H), 1.68 (1 H, ddd, J

H, d, J 7, 2-CH₃), 0.88 (3 H, d, J 6, 9-H₃), 0.89 [9 H, s, SiC- 4, 8 and 14, 7-H′), 1.94 (2 H, m, 4-H₂), 2.47 (1 H, m, 2-H), 2.95

(CH₃)₃], 1.22–1.95 (7 H, m, 4-H₂, 5-H₂, 7-H₂and 2-H), 3.24 (1 (1 H, br. s, OH), 3.63 (3 H, s, OCH₃), 3.94 (2 H, m, 3-H and

H, br. s, OH), 3.46 (3 H, m, 6-H and 1-H₂), 3.92 (2 H, m, 3-H 8-H) and 4.06 (1 H, m, 6-H); δ_C(CDCl₃, 75 MHz) 13.5, 23.1,

and 8-H), 7.26–7.34 (6 H, m, ArH) and 7.58–7.64 (4 H, m, Ar- 28.8, 30.4, 42.5, 45.2, 51.6, 65.1, 77.2, 81.0 and 175.2; m/z (CI)

H); δ_C(CDCl₃, 75 MHz) 13.7, 19.3, 24.2, 26.9, 30.4, 30.6, 40.9, 234 (M⁺+ 18, 58%) and 217 (M⁺+ 1, 100).

46.0, 67.6, 68.4, 76.7, 85.4, 127.3, 127.4, 129.3, 129.4, 134.8

A solution of nonactin (25 mg, 0.035 mmol) in methanol

(2.85 mL) and aqueous sulfuric acid (0.15 mL, 5% v/v) was

and 135.8; m/z (CI) 427 (M⁺, 8%), 349 (97) and 271(100).

M^ETHYL(2R,3R,6S,8S)-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-2- heated under reflux for 48 h then allowed to cool to room

(15). Pyridinium dichromate (0.42 g, temperature.¹⁵DCM (5 mL) was added and the organic phase

METHYLNONANOATE

1.12 mmol) was added to the alcohol 14 (0.14 g, 0.32 mmol) in was washed with a saturated aqueous sodium bicarbonate

N,N-dimethylformamide (3 mL) at room temperature and the (5 mL), dried (MgSO₄) and concentrated under reduced

reaction mixture stirred for 24 h. Water (3 mL) and saturated pressure. Chromatography of the residue using 1 : 1 light

aqueous sodium carbonate (25 mL) were added and the petroleum : ether gave racemic methyl nonactate ( )-(2) (20 mg,

aqueous phase was acidified to pH 1 using aqueous hydrogen 66%) as a colourless oil (Found; M⁺, 216.1359. C₁₁H₂₀O₄

chloride (50 mL, 3.5 M) then extracted with ethyl acetate (4 × requires M, 216.1362) with spectroscopic data identical to

20 mL). The organic extracts were dried (MgSO₄) and concen- those of the (−)-enantiomer.

trated under reduced pressure. Chromatography of the residue

TERT-BUTYL (3R)-3-[N-BENZYL-N-(R)-α-METHYLBENZYL]AMINOHEXANOATE

2 : 1 light petroleum : ether (with 1% v/v of acetic acid) gave the (21). N-Butyllithium was added to (R)-N-benzyl-α-methylbenzyl-

corresponding acid (0.12 g, 82%) as a colourless oil, ν_max/cm⁻¹amine (29.5 g, 139.4 mmol) in anhydrous THF (200 mL) at

1709, 1110 and 703; δ_H(CDCl₃, 300 MHz) 1.08 [12 H, m, SiC- −78 °C and the solution stirred at −78 °C for 30 min. tert-Butyl

(CH₃)₃and 9-H₃], 1.22 (3 H, d, J 7, 2-CH₃), 1.40–2.18 (6 H, m, (E)-hex-2-enoate (20)¹⁷(15.8 g, 93 mmol) in THF (100 mL) was

4-H₂, 5-H₂and 7-H₂), 2.47 (1 H, m, 2-H), 3.85 (1 H, m, 3-H), added and, after 2 h, aqueous ammonium chloride (50 mL)

4.04 (1 H, m, 6-H), 4.09 (1 H, m, 8-H), 7.43 (6 H, m, ArH), was added. The mixture was allowed to warm to ambient temp-

7.70–7.66 (4 H, m, ArH) and 9.90 (1 H, br. s, OH).

erature and concentrated to approximately one third of its orig-

Trimethylsilyldiazomethane (0.23 mL, 2.0 M in hexanes, inal volume under reduced pressure. Ether was added and the

0.6 mmol) was added to the acid (0.1 g, 0.23 mmol) in aqueous layer was extracted with ether. The organic extracts

benzene (4 mL) and methanol (1 mL) at room temperature and were washed with water and brine then dried (MgSO₄). After

the solution stirred for 30 min. Water (5 mL) was added and concentration under reduced pressure, chromatography of the

the organic phase was washed with brine (5 mL), dried residue using 20 : 1 light petroleum : ether gave the title com-

(MgSO₄) and concentrated under reduced pressure. The pound 21 (31.5 g, 89%) as a pale yellow liquid, [α]²_D³+12.4 (c 0.9

residue was chromatographed 6 : 1 light petroleum : ether to in CHCl₃) (Found: M⁺, 381.2674. C₂₅H₃₅NO₂requires M,

yield the title compound 15 (0.08 g, 78%) as a colourless oil, 381.2668); δ_H(CDCl₃, 300 MHz) 0.9 (3 H, t, J 7.1, 6-H₃), 1.37 (3

[α]²_D¹−3.7 (c 1.8 in DCM) (Found: M⁺+ H, 441.2468. H, d, J 7, CHCH₃), 1.2–1.7 [13 H, m, C(CH₃)₃, 4-H₂and 5-H₂],

C₂₆H₃₉O₄Si requires M, 441.2461); ν_max/cm⁻¹1740, 1108, 1462, 1.90 (1 H, dd, J 14.6, 9.1, 2-H), 2.0 (1 H, dd, J 14.6, 3.7, 2-H′),

1430, 1376, 1260, 1196, 1065, 822, 736 and 703; δ_H(CDCl₃, 3.36 (1 H, m, 3-H), 3.52 and 3.84 (each 1 H, d, J 15, PhHCH),

300 MHz) 1.07 [12 H, m, SiC(CH₃)₃and 9-H₃], 1.13 (3 H, d, J 7, 3.86 (1 H, q, J 7, NCH) and 7.2–7.5 (10 H, m, ArH); δ_C(CDCl₃,

2-CH₃), 1.20–1.80 (4 H, m, 4-H₂and 5-H₂), 1.90 (2 H, m, 7-H₂), 75 MHz) 14.0, 20.0, 20.4, 28.0, 35.7, 37.7, 50.0, 53.6, 58.2, 79.8,

2.51 (1 H, quin, J 7, 2-H), 3.68 (3 H, s, OCH₃), 4.00 (3 H, m, 3- 126.4, 126.8, 127.9, 128.0(2), 128.1, 142.0, 143.1 and 172.2; m/z

H, 6-H and 8-H), 7.36–7.48 (6 H, m, ArH) and 7.69–7.76 (4 H, (EI) 382 (M⁺+ 1, 5%), 381 (M⁺, 5), 338 (50), 266 (45) and 105

m, ArH); δ_C(CDCl₃, 75 MHz) 13.2, 19.3, 24.0, 26.9, 28.4, 31.2, (100).

45.2, 46.1, 51.5, 67.8, 76.4, 80.0, 127.3, 127.4, 129.3, 134.3,

134.9, 135.8 and 175.2; m/z, (CI) 458 (M⁺+ 18, 3%), 441 (M⁺+ added to Pd(OH)₂on carbon (20%, 4 g) with gentle stirring.

1, 7) and 285 (100). Ammonium formate (31.5 g, 0.5 mol) was added as a solid in

TERT-BUTYL (R)-3-AMINOHEXANOATE (22). Methanol (100 mL) was

(−)-M^ETHYLNONACTATE (2).³The silyl ether 15 (62 mg, batches (CAUTION gas evolved) over 30 min. After 15 min, the

0.14 mmol) was added to tetrabutylammonium fluoride amine 21 (7.62 g, 19.97 mmol) in methanol (100 mL) was

(0.7 mL 1.0 M in THF, 0.7 mmol) and the solution was stirred added over 5 min and the mixture was stirred for 1 h. Formic

for 7 h at room temperature. Water (0.5 mL) was added and acid (12 mL, 0.319 mol) was added in batches (ca. 1 mL every

the organic phase washed with brine (0.5 mL) and then dried 5 min) (CAUTION gas evolved rapidly). After the addition was

(MgSO₄). After concentration under reduced pressure, chrom- completed, the mixture was stirred for 2 h at room temperature

atography of the residue using 2 : 1 light petroleum : ether gave then filtered through a plug of Celite® that was washed with

the title compound 2 (23 mg, 78%) as a colourless oil, [α]²_D¹methanol and CHCl₃. The filtrate was concentrated under

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9717

Paper

reduced pressure to give a white solid that was dissolved in mixture stirred at −78 °C for 5 min. The hexanol 24 (2.89 g,

aqueous sodium hydroxide (10%, 150 mL). The aqueous sol- 11.5 mmol) in DCM (9 mL) was added and the mixture stirred

ution was extracted with DCM (3 × 75 mL) and the organic at −78 °C for 20 min. Et₃N (6.1 mL, 44 mmol) was added and

layer washed with water and brine then dried (MgSO₄). Con- the solution was stirred for 10 min then allowed to warm to

centration under reduced pressure gave the title compound 22 room temperature. Water was added and the aqueous phase

(3.72 g, 91%) as colourless liquid, [α]²_D⁴−16.6 (c 1 in CHCl₃) extracted with DCM. The organic extracts were washed with

(Found: M⁺+ H, 188.1652. C₁₀H₂₂NO₂requires M, 188.1650); aqueous ammonium chloride, water and brine then dried

ν_max/cm⁻¹3300, 1726, 1459 1367, 1318, 1255, 1153 and 843; δ_H(MgSO₄). Concentration under reduced pressure gave the title

(CDCl₃, 300 MHz) 0.85 (3 H, t, J 5.9, 6-H₃), 1.39 [9 H, s, compound 25 (2.87 g, 99%) as a white solid that was used

C(CH₃)₃], 1.2–1.46 (4 H, m, 4-H₂and 5-H₂), 2.09 (1 H, dd, immediately (Found: M⁺+ H, 250.1447. C₁₄H₂₀NO₃requires M,

J 15.5, 8.8, 2-H), 2.30 (1 H, dd, J 15.5, 4.0, 2-H′) and 3.10 (1 H, 250.1443); ν_max/cm⁻¹3327, 1722, 1693, 1530, 1455, 1257, 1229,

m, 3-H); δ_C(CDCl₃, 75 MHz) 13.9, 19.0, 28.0, 39.6, 43.8, 47.9, 1085, 1027, 739 and 698; δ_H(CDCl₃, 300 MHz) 0.85 (3 H, t, J 7,

80.2 and 171.9; m/z (CI) 188 (M⁺+ 1, 100%) and 132 (70).

6-H₃), 1.2–1.5 (4 H, m, 4-H₂and 5-H₂), 2.56 (2 H, m, 2-H₂), 4.02

TERT-BUTYL

(R)-3-(N-BENZYLOXYCARBONYL)AMINOHEXANOATE

(23). (1 H, m, 3-H), 4.90 (1 H, br. m, NH), 5.01 (2 H, s, PhCH₂), 7.27

Benzyl chloroformate (0.8 mL, 5.61 mmol) was added to the (5 H, m, ArH) and 9.68 (1 H, s, 1-H); δ_C(CDCl₃, 75 MHz) 13.7,

amine 22 (1.05 g, 5.61 mmol), potassium carbonate (3.87 g, 19.2, 36.9, 46.8, 48.8, 66.7, 128.0, 128.1, 128.4, 136.3, 155.8

28.07 mmol), water (60 mL) and ether (60 mL) at 0 °C. The and 200.9; m/z (CI) 250 (M⁺+ 1, 100%).

mixture was stirred at 0 °C for 30 min, allowed to warm to

(2R,6S,8R,3Z)-1-B^ENZYLOXY-8-(N-BENZYLOXYCARBONYL)AMINO-2-METHYL-

room temperature and then stirred for a further 3 h. The ^UNDEC-3-EN-6-OL (26). Tin(IV) chloride (1 M in DCM, 1.35 mL,

aqueous layer was extracted with ether and the organic extracts 1.35 mmol) was added to the stannane 3 (0.65 g, 1.35 mmol)

were washed with water and brine then dried (MgSO₄). After in DCM (15 mL) at −78 °C. After 5 min, a cooled (0 °C) solu-

concentration under reduced pressure, chromatography of the tion of aldehyde 25 (307 mg, 1.23 mmol) in DCM (10 mL) was

residue using 15 : 1 light petroleum : ether gave the title com- added and the mixture was stirred for 50 min at −78 °C.

pound 23 (1.58 g, 88%) as a colourless liquid, [α]²_D¹+15.6 (c 1.14 Methanol (0.75 mL) and aqueous sodium bicarbonate (3 mL)

in CHCl₃) (Found: M⁺+ H, 322.2022. C₁₈H₂₈NO₄requires were added and the mixture was allowed to warm to room

322.2018); ν_max/cm⁻¹3333, 1725, 1532, 1455, 1367, 1255, 1161, temperature and was stirred for 1 h. Water (5 mL) was added

1102, 738 and 697; δ_H(CDCl₃, 300 MHz) 0.84 (3 H, t, J 7, 6-H₃), and the aqueous phase extracted with DCM. The organic

1.2–1.48 [13 H, m, C(CH₃)₃, 4-H₂and 5-H₂), 2.35 (2 H, m, 2- extracts were washed with water (15 mL), dried (MgSO₄) and

H₂), 3.89 (1 H, m, 3-H), 5.01 (2 H, s, PhCH₂O), 5.18 (1 H, br. d, concentrated under reduced pressure. Chromatography of the

J 6.5, NH) and 7.26 (5 H, m, ArH); δ_C(CDCl₃, 75 MHz) 13.7, residue using light petroleum : ether (gradient elution 10 : 1 to

19.2, 28.0, 36.7, 40.2, 48.1, 66.4, 80.9, 127.9, 128.4, 136.0, 155.7 3 : 1) gave the title compound 26 (352 mg, 64%) as a colourless

and 171.0; m/z (CI) 322 (M⁺+ 1, 30%) and 266 (100).

liquid, [α]²_D¹+1.7 (c 1.87 in CHCl₃) (Found: M⁺+ H, 440.2806.

(R)-3-(N-B^{ENZYLOXYCARBONYL})AMINOHEXAN-1-OL (24). Lithium alu- C₂₇H₃₈NO₄requires M, 440.2800); ν_max/cm⁻¹3404, 3327, 1698,

minium hydride (1 M in ether, 4.9 mL, 4.9 mmol) was added 1530, 1453, 1255, 1233, 1091, 739 and 698; δ_H(CDCl₃,

to the ester 23 (1.58 g, 4.92 mmol) in ether (8 mL) at 0 °C. The 500 MHz) 0.9 (6 H, m, 2-CH₃and 11-H₃), 1.26–1.66 (6 H, m, 7-

mixture was stirred for 10 min at 0 °C, allowed to warm to H₂, 9-H₂and 10-H₂), 2.25 (2 H, m, 5-H₂), 2.87 (1 H, m, 2-H),

room temperature and stirred for a further 2 h. The mixture 3.18 (1 H, t, J 9, 1-H), 3.2 (1 H, br. s, OH, exchangeable with

was cooled to 0 °C and water (1 mL), aqueous sodium hydrox- D₂O), 3.36 (1 H, dd, J 9 and 5, 1-H′), 3.64 (1 H, m, 6-H), 3.76

ide (2 mL) and water (2 mL) were added. The mixture was (1 H, m, 8-H), 4.48 and 4.53 (each 1 H, d, J 12, PhHCH), 4.90

warmed to room temperature, stirred for 45 min, then filtered (1 H, br. m, NH), 5.09 (2 H, s, PhCH₂OCO), 5.34 (1 H, t, J 10, 3-

through Celite®. The aqueous layer was extracted with ether H), 5.46 (1 H, m, 4-H) and 7.34 (10 H, m, ArH); δ_C(CDCl₃,

and the organic extracts were washed with water and brine 75 MHz) 13.9, 17.2, 18.8, 32.3, 36.0, 38.0, 42.5, 49.5, 66.4, 69.2,

then dried (MgSO₄). Concentration under reduced pressure 73.0, 74.8, 126.0, 127.6, 127.7, 127.9, 128.3, 128.4, 136.5 and

gave the title compound 24 (0.98 g, 80%) as a white solid, mp 156.2; m/z (CI) 440 (M⁺+ 1, 15%) and 332 (100).

61 °C, [α]²_D¹−13.6 (c 0.89 in CHCl₃) (Found: M⁺+ H, 252.1597.

(2S,3S,4S,6R,8R)-1-B^ENZYLOXY-8-(N-BENZYLOXYCARBONYLAMINO)-3,6-

C₁₄H₂₂NO₃requires M, 252.1600); ν_max/cm⁻¹3309, 1688, 1544, EPOXY-2-METHYL-4-PHENYLSELENOUNDECANE (27). Tin(IV) chloride

1264, 1050, 732 and 694; δ_H(CDCl₃, 300 MHz) 0.95 (3 H, t, J 7, (1 M in DCM, 113 μL, 0.113 mmol) and PhSeCl (200 mg,

6−H₃), 1.44 (4 H, m, 4-H₂and 5-H₂), 1.88 (2 H, m, 2-H₂), 3.26 1.05 mmol) were added to the alkenol 26 (482 mg, 1.13 mmol)

(1 H, br. s, OH), 3.66 (2 H, m, 1-H₂), 3.86 (1 H, m, 3-H), 4.76 (1 in DCM (20 mL) at room temperature. After 3 h, more tin(^IV)

H, br. m, NH), 5.13 and 5.14 (each 1 H, d, J 12.1, PhHCH) and chloride (1 M in DCM, 113 μL, 0.113 mmol) and PhSeCl

7.38 (5 H, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 19.2, 37.6, 38.6, 47.8, (60 mg, 0.31 mmol) were added and the mixture was stirred at

58.8, 66.9, 128.0, 128.1, 128.5, 136.3 and 157.3; m/z (CI) 252 room temperature for 15 h. Aqueous sodium bicarbonate was

(M⁺+ 1, 20%), 161 (40) and 144 (100).

added and the aqueous phase was extracted with DCM. The

(R)-3-(N-B^{ENZYLOXYCARBONYL})AMINOHEXANAL (25). DMSO (1.8 mL, organic extracts were washed with water and brine, then dried

23.7 mmol) in DCM (5 mL) was added to oxalyl chloride (MgSO₄). After concentration under reduced pressure, chrom-

(1.06 mL, 12.13 mmol) in DCM (17 mL) at −78 °C and the atography of the residue using 10 : 1 light petroleum : ether

9718 | Org. Biomol. Chem., 2012, 10, 9709–9733

This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry

gave the title compound 27 (167 mg, 25%) as a colourless oil 85.13 mmol) in THF (500 mL) at room temperature and the

(Found: M⁺, 595.2207. C₃₃H₄₁NO₄⁸⁰Se requires M, 595.2204); mixture stirred for 2 h. MeI (46 g, 324 mmol) was added drop-

ν_max/cm⁻¹3333, 1704, 1536, 1454, 1260, 1231, 1089, 1072, wise and the mixture stirred overnight. Water and ether were

1023, 737 and 695; δ_H(CDCl₃, 300 MHz) 0.94 (3 H, t, J 7.1, 11- added and the aqueous phase was extracted with ether. The

H₃), 1.08 (3 H, d, J 6.7, 2-CH₃), 1.38 and 1.50 (each 2 H, m), organic extracts were washed with water and brine then dried

1.82 (2 H, t, J 6.6), 2.0 (1 H, dd, J 13.8 and 4.2, 5-H), 2.19 (1 H, (MgSO₄). Concentration under reduced pressure gave the title

m, 2-H), 2.70 (1 H, m, 5-H′), 3.52 (1 H, m, 1-H), 3.64 (3 H, m), compound 30 (28.7 g, 99%) as a colourless liquid, [α]²_D²−35.8 (c

3.8 and 4.01 (each 1 H, m), 4.40 and 4.51 (each 1 H, d, J 12.2, 1.23 in CHCl₃) (Found: M⁺+ H, 356.1902. C₁₈H₃₀NO₄S requires

PhHCH), 4.89 (1 H, br. m, NH), 5.06 and 5.14 (each 1 H, d, J 356.1895); ν_max/cm⁻¹1727, 1458, 1342, 1160, 1090, 939, 816

12.2, PhHCHOCO), 7.32 (13 H, m, ArH) and 7.56 (2 H, m, and 693; δ_H(CDCl₃, 300 MHz) 0.9 (3 H, t, J 7.3, 6-H₃),

ArH); δ_C(CDCl₃, 300 MHz) 13.9, 14.4, 18.8, 37.1, 38.1, 40.5, 1.22–1.42 (4 H, m, 4-H₂and 5-H₂), 1.46 [9 H, s, C(CH₃)₃], 2.05

41.5, 46.0, 49.9, 66.4, 72.8, 73.0, 76.1, 84.2, 127.3, 127.4, 127.9, (1 H, dd, J 14.7, 5.2, 2-H), 2.2 (1 H, dd, J 14.7, 8.9, 2-H′), 2.42 (3

128.2, 128.4, 129.1 and 134.1; m/z (EI) 594 (M⁺− 1, 3%), 487 H, s, ArCH₃), 2.68 (3 H, s, NCH₃), 4.32 (1 H, m, 3-H) and 7.3

(5), 398 (8), 330 (15) and 91 (100).

and 7.74 (each 2 H, d, J 8.3, ArH); δ_C(75 MHz, CDCl₃) 13.6,

(2S,3R,6S,8R)-1-B^ENZYLOXY-8-(BENZYLOXYCARBONYLAMINO)-3,6-EPOXY-

19.2, 21.4, 27.9, 28.1, 34.1, 39.0, 53.9, 80.8, 127.1, 129.5, 136.8,

2-^{METHYLUNDECANE}(28). Tributyltin hydride (47 μL, 0.178 mmol) 143.0 and 170.0; m/z (EI) 356 (M⁺+ 1, 20%), 312 (30), 300 (90),

and AIBN (cat.) were added to the phenylselenide 27 (53 mg, 240 (90) and 144 (100).

0.089 mmol) in degassed toluene (7 mL) and the mixture was

(R)-3-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]HEXAN-1-OL

(31).

heated under reflux for 1 h. After concentration under reduced Lithium aluminium hydride (1 M in Et₂O, 124 mmol, 124 mL)

pressure, chromatography of the residue using 3 : 1 light was added to the ester 30 (55 g, 155 mmol) in dry ether

petroleum : ether gave the title compound 28 (25 mg, 64%) as a (400 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C at

white solid, ν_max/cm⁻¹3331, 1723, 1530, 1517, 1454, 1256, room temperature for 1 h and was then cooled to 0 °C. Water

1230, 1091, 1069, 737 and 698; δ_H(CDCl₃, 300 MHz) 0.94 (3 H, (10 mL) was added, followed by aqueous sodium hydroxide

t, J 7, 11-H₃), 0.98 (3 H, d, J 6.7, 2-CH₃), 1.28–1.72 (8 H, m), 1.9 (10%, 10 mL) and water (50 mL). The reaction mixture was

(2 H, m), 2.04 (1 H, m, 2-H), 3.38 (1 H, dd, J 9 and 7, 1-H), 3.62 stirred at room temperature for 1 h, and then was filtered

(1 H, dd, J 9 and 4.5, 1-H′), 3.7 (2 H, m, 3-H, 6-H), 3.9 (1 H, through Celite®. The aqueous phase was extracted with ether

quin, J 6.5, 8-H), 4.49 (2 H, s, PhCH₂O), 4.92 (1 H, br. m, NH), and the organic extracts were washed with water and brine,

5.12 (2 H, s, PhCH₂OCO) and 7.36 (10 H, m, ArH); δ_C(CDCl₃, then dried (MgSO₄). After concentration under reduced

75 MHz) 13.7, 13.9, 18.8, 25.1, 28.4, 31.5, 38.1, 39.0, 41.0, 49.8, pressure, chromatography of the residue using 1 : 1 light

66.3, 72.9, 73.1, 81.0, 127.3, 127.4, 127.9(2), 128.2, 128.4, petroleum : ether gave the title compound 31 (41.66 g, 94%) as a

136.7, 138.8 and 156.1.

colourless oil, [α]_D²²−7.8 (c 1.22 in CHCl₃) (Found: M⁺+ H,

TERT-BUTYL

(R)-3-(TOLUENE-4-SULFONYLAMINO)HEXANOATE

(29). 286.1473. C₁₄H₂₄NO₃S requires M, 286.1477); ν_max/cm⁻¹3387,

Toluene 4-sulfonyl chloride (3.35 g, 17.65 mmol) in DCM 1598, 1465, 1330, 1161, 1149, 1089, 1054, 942, 816 and 715; δ_H

(10 mL), Et₃N (1.77 mL, 17.65 mmol) and DMAP (0.22 g) were (CDCl₃, 300 MHz) 0.75 (3 H, t, J 7, 6-H₃), 0.82–1.36 (4 H, m,

added to the aminohexanoate 22 (2.20 g, 11.76 mmol) in DCM 4-H₂and 5-H₂), 1.48 and 1.72 (each 1 H, m, 2-H), 2.44 (3 H, s,

(20 mL) at 0 °C. The mixture was stirred at room temperature ArCH₃), 2.5 (3 H, s, NCH₃), 2.8 (1 H, br. s, OH), 3.62 and 3.77

for 24 h before being diluted with water (10 mL). The aqueous (each 1 H, m 1-H), 4.02 (1 H, m, 3-H) and 7.32 and 7.72 (each 2

layer was extracted with DCM (3 × 10 mL) and the organic H, d, J 8.4, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 19.6, 21.4, 27.4, 34.3

extracts were washed with saturated aqueous sodium bicarbon- (2), 53.5, 58.5, 126.8, 129.5, 136.9 and 143.2; m/z (EI) 286 (M⁺+

ate (25 mL) and water (25 mL), then dried (MgSO₄). After con- 1, 20%), 242 (95), 240 (85), 155 (80) and 91 (100).

centration under reduced pressure, chromatography of the

(R)-3-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]HEXANAL

(32).

residue with ether : light petroleum (gradient elution 1 : 10 to DMSO (0.69 g, 8.78 mmol, 0.62 mL) was added to oxalyl chlor-

4 : 10) gave the title compound 29 (3.80 g, 95%) as an oil, R_f= ide (0.67 g, 0.46 mL, 5.27 mmol) in DCM (20 mL) at −78 °C

0.41 (50% ether : light petroleum), [α]²_D⁶+35 (c 0.5 in CHCl₃) and the mixture stirred for 5 min. The alcohol 31 (1.01 g,

(Found: M⁺+ H, 342.1740. C₁₇H₂₈NO₄S requires M, 342.1739); 3.54 mmol) in DCM (10 mL) was added and the resulting

ν_max/cm⁻¹3289, 1727, 1455, 1368, 1329, 1160, 1093, 1034, 959 mixture stirred at −78 °C for 20 min. Et₃N (1.77 g, 2.45 mL,

and 815; δ_H(300 MHz, CDCl₃) 0.84 (3 H, t, J 7.1, 6-H₃), 17.55 mmol) was added at −78 °C and the mixture stirred for a

1.16–1.54 [13 H, m, 4-H₂, 5-H₂, C(CH₃)₃], 2.26 (1 H, dd, J 15.9, further 10 min at −78 °C and then for 1.5 h at room tempera-

5.5, 2-H), 2.34 (1 H, dd, J 15.9, 4.4, 2-H′), 2.46 (3 H, s, ArCH₃), ture. Water (10 mL) was added and the aqueous layer was

3.52 (1 H, m, 3-H), 5.32 (1 H, d, J 9.1, NH) and 7.33 and 7.80 extracted with DCM (3 × 10 mL). The organic extracts were

(each 2 H, d, J 7.8, ArH); δ_C(75 MHz, CDCl₃) 13.5, 18.9, 21.4, washed with saturated aqueous ammonium chloride (20 mL),

28.0, 36.6, 39.3, 50.5, 81.3, 126.9, 129.5, 138.2, 143.1, 170.7; water (20 mL) and brine (20 mL). After drying (MgSO₄), con-

m/z (CI) 359 (M⁺+ 18, 23%), 342 (M⁺+ 1, 6%) and 303 (100).

centration under reduced pressure gave the title compound 32

TERT-BUTYL (R)-3-[N-METHYL-N-(TOLUENE-4-SULFONYL)AMINO]HEXANO- (0.99 g, 99%) as a pale oil, which was used immediately, R_f=

^ATE(30). The sulfonamide 29 (27.65 g, 81.18 mmol) in THF 0.55 (50% ether : light petroleum); [α]_D²⁶−6.0 (c 1.0 in CHCl₃)

(500 mL) was added to

suspension of NaH (3.4 g, (Found: M⁺+ H, 284.1321. C₁₄H₂₂NO₃S requires M, 284.1320];

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9719

Paper

ν_max/cm⁻¹1723, 1598, 1462, 1383, 1335, 1213, 1162, 1089, 928, 7.20–7.40 (10 H, m, ArH), 7.53 (2 H, m, ArH) and 7.72 (2 H, d, J

817 and 714; δ_H(CDCl₃, 300 MHz) 0.87 (3 H, t, J 7.3, 6-H₃), 8.2, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 14.4, 19.5, 21.5, 27.7, 33.9,

1.20–1.40 (4 H, m, 4-H₂and 5-H₂), 2.34 (1 H, ddd, J 16, 8, 2, 2- 37.2, 38.6, 40.1, 46.3, 54.5, 72.9, 73.1, 75.1, 83.9, 127.0, 127.1,

H), 2.45 (3 H, s, ArCH₃), 2.47 (1 H, m, 2-H′), 2.7 (3 H, s, NCH₃), 127.3, 127.4, 128.2, 129.0, 129.4, 129.5, 133.8, 137.2, 138.8 and

4.48 (1 H, quin, J 7, 3-H), 7.32 and 7.7 (each 2 H, d, J 7.8, ArH) 142.7; m/z (EI) 629 (M⁺, 0.25%), 474 (2), 240 (40) and 91 (100).

and 9.64 (1 H, m, 1-H); δ_C(CDCl₃, 75 MHz) 13.5, 19.3, 21.4,

28.0, 34.5, 46.3, 51.8, 127.0, 129.6, 136.6, 143.4 and 199.8; m/z AMINO]-3,6-EPOXY-2-METHYLUNDECANE

(EI) 284 (M⁺+ 1, 20%) and 240 (100).

(18.2 mL, 67.63 mmol) and AIBN (cat.) were added to the phe-

(2S,3R,6S,8R)-1-B^ENZYLOXY-8-[N-METHYL-N-(TOLUENE-4-SULFONYL)-

(35). Tributyltin

hydride

(2R,6S,8R,3Z)-8-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]-1-BENZYL- nylselenide 34 (21.27 g, 33.81 mmol) in benzene (1 L) and the

^OXY-2-METHYLUNDEC-3-EN-6-OL (33). Tin(IV) chloride (1 M in DCM, mixture heated under reflux for 45 min. The mixture was

19.6 mL, 19.6 mmol) was added to the stannane 3 (9.41 g, allowed to cool to room temperature and was concentrated

19.64 mmol) in DCM (200 mL) at −78 °C. After 5 min, the alde- under reduced pressure. Chromatography of the residue using

hyde 32 (5.05 g, 17.86 mmol) in DCM (100 mL), cooled to 0 °C, light petroleum : ether (gradient elution 10 : 1 to 3 : 1) gave the

was added and the solution was stirred for 50 min at −78 °C. title compound 35 (15.03 g, 94%) as a colourless oil, [α]²_D¹−24.5

Methanol (5 mL) and aqueous sodium bicarbonate (50 mL) (c 1.27 in CHCl₃) (Found: M⁺+ H, 474.2683. C₂₇H₄₀NO₄S

were added and the mixture was allowed to warm to room requires M, 474.2678); ν_max/cm⁻¹1598, 1495, 1454, 1337, 1152,

temperature then stirred for 1 h. Water (100 mL) was added 1090, 927 and 815; δ_H(CDCl₃, 500 MHz) 0.84 (3 H, t, J 7, 11-

and the aqueous layer was extracted with DCM. The organic H₃), 0.96 (3 H, d, J 7, 2-CH₃), 1.15 (1 H, m), 1.25 (2 H, m),

extracts were washed with water (200 mL), dried (MgSO₄) and 1.30–1.50 (3 H, m), 1.56 and 1.87 (each 2 H, m), 2.02 (1 H, m,

concentrated under reduced pressure. Chromatography of the 2-H), 2.4 (3 H, s, ArCH₃), 2.67 (3 H, s, NCH₃), 3.36 (1 H, dd, J

residue using light petroleum : ether (gradient elution 10 : 1 to 9.3 and 7.5, 1-H), 3.63 (2 H, m, 1-H′ and 3-H), 3.76 and 3.99

3 : 1) gave the title compound 33 (5.4 g, 64%) as an oil, [α]²_D¹(each 1 H, quin, J 7.0, 6-H or 8-H), 4.55 (2 H, s, PhCH₂), 7.26 (2

−18.6 (c 1.53 in CHCl₃) (Found: M⁺+ H, 474.2678. C₂₇H₄₀NO₄S H, d, J 8.3, ArH), 7.34 (5 H, m, ArH) and 7.69 (2 H, d J 8.3,

requires M, 474.2678); ν_max/cm⁻¹3483, 1454, 1335, 1162, 1151, ArH); δ_C(CDCl₃, 125 MHz) 13.3, 13.6, 19.4, 21.1, 27.4, 28.2,

1089, 928, 815, 718 and 699; δ_H(CDCl₃, 400 MHz) 0.83 (3 H, t, 30.8, 33.8, 38.0, 38.8, 54.5, 72.7, 72.9, 75.8, 80.4, 126.9, 127.0,

J 7, 11-H₃), 0.92 (3 H, d, J 6.5, 2-CH₃), 1.05–1.55 (6 H, m, 7-H₂, 127.2, 128.0, 129.2, 137.1, 138.6 and 142.5; m/z (CI) 491 (M⁺+

9-H₂, 10-H₂), 2.21 (2 H, m, 5-H₂), 2.42 (3 H, s, ArCH₃), 2.67 (3 18, 30%) and 474 (M⁺+ 1, 100%).

H, s, NCH₃), 2.85 (1 H, m, 2-H), 3.04 (1 H, br. s, OH), 3.18 (1 H,

(2S,3R,6S,8R)-8-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]-3,6-EPOXY-

t, J 8.5, 1-H), 3.35 (1 H, dd, J 8.5 and 5, 1-H′), 3.6 (1 H, m, 6-H), 2-^{METHYLUNDECAN}-1-OL (36). The benzyl ether 35 (7.2 g,

4.07 (1 H, quin, J 7, 8-H), 4.53 (2 H, s, PhCH₂), 5.33 (1 H, t, J 15.22 mmol) in ethanol (50 mL) and acetic acid (3 mL) was

10, 3-H), 5.44 (1 H, m, 4-H), 7.28 and 7.72 (each 2 H, d, J 7.8, added to Pd/C (10%, 2.5 g) and ethanol (500 mL) and the sol-

ArH) and 7.34 (5 H, m, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 17.2, ution stirred under an atmosphere of hydrogen for 15 h. The

19.6, 21.4, 27.7, 32.3, 34.0, 35.6, 39.3, 54.4, 68.1, 73.0, 74.7, catalyst was removed by filtration through Celite® and the fil-

126.0, 127.2, 127.5, 127.7, 128.3, 129.4, 136.3, 137.1, 138.0 and trate was evaporated to give the title compound 36 (5.7 g, 91%)

142.8; m/z (CI) 491 (M⁺+ 18, 15%) and 474 (M⁺+ 1, 100).

(2S,3S,4S,6R,8R)-1-B^ENZYLOXY-8-[N-METHYL-N-(TOLUENE-4-SULFONYL)- H, 384.2203. C₂₀H₃₄NO₄S requires M, 384.2208); δ_H(CDCl₃,

(34). Tin(IV) 500 MHz) 0.79 (3 H, t, J 7, 11-H₃), 0.82 (3 H, d, J 7, 2-CH₃),

as a colourless liquid, [α]²_D⁵−5.5 (c 1.73 in CHCl₃) (Found: M⁺+

AMINO]-3,6-EPOXY-2-METHYL-4-PHENYLSELENOUNDECANE

chloride (1 M in DCM, 12.4 mL, 12.4 mmol) and PhSeCl 1.00–1.20 (3 H, m), 1.28 (1 H, m), 1.44 (2 H, m), 1.56 (1 H, m),

(14.2 g, 74.33 mmol) were added in batches to the alkenol 33 1.71 (2 H, m), 2.0 and 2.08 (each 1 H, m), 2.41 (3 H, s, ArCH₃),

(29.3 mg, 61.9 mmol) in DCM (1 L) at room temperature and 2.65 (3 H, s, NCH₃), 3.32 (1 H, br. s, OH, exchangeable with

the solution stirred for 6 h. Aqueous sodium bicarbonate was D₂O), 3.58 (3 H, m, 1-H₂and 3-H), 3.86 and 3.91 (each 1 H, m,

added and the mixture stirred for another 30 min. The organic 6-H or 8-H) and 7.28 and 7.68 (each 2 H, d, J 8.3, ArH); δ_C

layer was washed with water and brine, dried (MgSO₄) and con- (CDCl₃, 125 MHz) 13.6, 13.7, 19.6, 21.4, 27.5, 30.2(2), 34.0,

centrated under reduced pressure. Chromatography of the 38.0, 40.9, 54.7, 68.2, 77.0, 85.1, 127.0, 129.4, 137.1 and 142.9;

residue using light petroleum : ether (gradient elution 10 : 1 to m/z (CI) 384 (M⁺+ 1, 100%).

3 : 1) gave the title compound 34 (16.8 g, 42%) as a colourless

(2R,3R,6S,8R)-8-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]-3,6-EPOXY-

liquid, [α]²_D¹+51.5 (c 1.09 in CHCl₃) (Found: M⁺, 629.2076. 2-^{METHYLUNDECANAL}(37). Following the procedure outlined for

C₃₃H₄₃NO₄S⁸⁰Se requires M, 629.2078); ν_max/cm⁻¹3061, 3029, the preparation of aldehyde 32, the alcohol 36 (144 mg,

1598, 1579, 1453, 1337, 1153, 1090, 927, 815, 736 and 695; δ_H0.376 mmol) was oxidised to the title compound 37 (129 mg,

(CDCl₃, 500 MHz) 0.86 (3 H, t, J 7, 11-H₃), 1.1 (3 H, d, J 6.7, 2- 90%) as an oil, that was used immediately without chromato-

CH₃), 1.10–1.42 (4 H, m, 9-H₂and 10-H₂), 1.61 and 1.76 (each graphy (Found: M⁺+ H, 382.2047. C₂₀H₃₂NO₄S requires M,

1 H, m, 7-H), 1.94 (1 H, ddd, J 14, 3.7, 1.6, 5-H), 2.19 (1 H, m, 382.2052); δ_H(CDCl₃, 300 MHz) 0.74 (3 H, t, J 7, 11-H₃), 0.99 (3

2-H), 2.44 (3 H, s, ArCH₃), 2.70 (4 H, m, 5-H′ and NCH₃), 3.54 H, d, J 7, 2-CH₃), 1.02–1.66 (8 H, m), 1.9–2.1 (2 H, m), 2.34 (4

(1 H, dd, J 8.9 and 7.0, 1-H), 3.60 (1 H, dd, J 9.7 and 4, 3-H), H, m, 2-H and ArCH₃), 2.59 (3 H, s, NCH₃), 3.76 (1 H, m), 3.86

3.75 (1 H, dd, J 9.0 and 3.3, 1-H′), 3.79 (1 H, m, 4-H), 3.97 (2 H, (2 H, m), 7.22 and 7.6 (each 2 H, d, J 8.1 ArH) and 9.67 (1 H, d,

m, 6-H and 8-H), 4.57 and 4.6 (each 1 H, d, J 12.1, PhHCH), J 2.5, 1-H); δ_C(CDCl₃, 75 MHz) 10.5, 13.7, 19.6, 21.4, 27.6, 29.1,

9720 | Org. Biomol. Chem., 2012, 10, 9709–9733

This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry

30.6, 34.0, 38.0, 51.6, 54.6, 77.0, 79.4, 127.1, 128.2, 129.4, 142.8 M⁺+ H, 330.2651. C₁₈H₃₆NO₄requires M, 330.2644); ν_max/cm⁻¹

and 204.3; m/z (CI) 399 (M⁺+ 18, 45%) and 382 (M⁺+ 1, 100).

3465, 1692, 1478, 1455, 1400, 1366, 1341, 1150, 1045, 873 and

(2S,3R,6S,8R)-1-B^ENZYLOXY-3,6-EPOXY-2-METHYL-8-(METHYLAMINO)- 770; δ_H(CDCl₃, 300 MHz) 0.85 (3 H, m, 2-CH₃), 0.93 (3 H, t, J

UNDECANE (38). Sodium (∼150 mg) and naphthalene (900 mg) 7, 11-H₃), 1.20–2.02 (12 H, m), 2.47 [9 H, s, C(CH₃)₃], 2.66 (1.2

were added to dimethoxyethane (6 mL) and the mixture soni- H, s, NCH₃), 2.69 (1.8 H, s, NCH₃), 3.62 (3 H, m), 3.79 (1 H, m),

cated at room temperature for 10 min then added to the sulfo- 4.09 (0.6 H, m, 8-H) and 4.24 (0.4 H, m, 8-H); δ_C(CDCl₃,

namide 35 (55 mg) in dimethoxyethane (2 mL) at −60 °C until 75 MHz) 13.7, 19.0(2), 28.4, 30.3, 34.9(2), 38.3, 38.7, 41.0, 52.4,

a dark green colour persisted. The mixture was stirred with a 68.2, 68.4, 85.2, 85.4 and 156.0; m/z (CI) 330 (M⁺+ 1, 5%), 286

glass covered magnetic bar for 1 h. Aqueous sodium bicarbon- (8) and 230 (100).

ate and solid K₂CO₃were added and the mixture was diluted

(2R,3R,6S,8R)-8-(N-^TERT-BUTOXYCARBONYL-N-METHYLAMINO)-3,6-

by adding ether. The aqueous layer was extracted with ether EPOXY-2-METHYLUNDECANAL (41). The Dess–Martin periodinane

and the organic extracts were dried (MgSO₄). After concen- (0.254 g, 0.599 mmol) was added to the alcohol 40 (0.116 g,

tration under reduced pressure, chromatography of the residue 0.353 mmol) in DCM (2.5 mL) and the mixture was stirred for

using 1 : 1 light petroleum : ether (with 1% Et₃N) gave the title 40 min at room temperature. Saturated aqueous sodium bicar-

compound 38 (32 mg, 85%) as an oil, [α]²_D¹−16.1 (c 1 in CHCl₃) bonate (3 mL) and saturated aqueous sodium bisulfite (3 mL)

(Found: M⁺+ H, 320.2586. C₂₀H₃₄NO₂requires M, 320.2589); were added and the mixture stirred for 20 min. The aqueous

ν_max/cm⁻¹3353, 1454, 1363, 1096, 1071, 735 and 697; δ_Hlayer was extracted with ether (3 × 10 mL) and the organic

(CDCl₃, 500 MHz) 0.96 (3 H, t, J 7.0, 11-H₃), 0.98 (3 H, d, J 7.0, extracts were washed with saturated aqueous sodium bicarbon-

2-CH₃), 1.25–1.35 (3 H, m), 1.40–1.50 (2 H, m), 1.55–1.65 (3 H, ate (10 mL), water (10 mL) and brine (10 mL), then dried

m), 1.80–2.00 (3 H, m), 2.40 (3 H, s, NCH₃), 2.58 (1 H, m, 8-H), (MgSO₄) and concentrated under reduced pressure to give the

3.44 (1 H, dd, J 9 and 7, 1-H), 3.64 (1 H, dd, J 9 and 4.6, 1-H′), aldehyde 41 (0.115 g, ca. 100%), as a colourless oil, a

3.77 (1 H, q, J 7.2, 3-H), 3.95 (1 H, m, 6-H), 4.57 (2 H, s, 60 : 40 mixture of rotamers, R_f= 0.46 (1 : 1 light petroleum :

PhCH₂) and 7.38 (5 H, m, ArH); δ_C(CDCl₃, 75 MHz) 13.6, 14.3, ether) (Found: M⁺+ H, 328.2488. C₁₈H₃₄NO₄requires M,

18.8, 28.3, 32.0, 33.5, 36.0, 39.0, 40.1, 58.5, 73.0, 73.1, 78.4, 328.2488); ν_max/cm⁻¹1729, 1691, 1458, 1398, 1366, 1151, 1063,

81.1, 127.3, 127.4, 128.2 and 138.8; m/z (CI) 320 (M⁺+ 1, 30%) 874 and 770; δ_H(CDCl₃, 300 MHz) 0.92 (3 H, t, J 7, 11-H₃), 1.09

and 86 (100).

(3 H, 2 × d, J 7, 2-CH₃), 1.18–1.74 (7 H, m), 1.47 [9 H, s, C

(2S,3R,6S,8R)-1-B^ENZYLOXY-8-(N-TERT-BUTOXYCARBONYL-N-METHYL- (CH₃)₃], 1.88 (1 H, m), 2.06 (2 H, m), 2.47 (1 H, m, 2-H), 2.64

^AMINO)-3,6-EPOXY-2-METHYLUNDECANE (39). Di-tert-butyl dicarbonate (1.2 H, s, NCH₃), 2.68 (1.8 H, s, NCH₃), 3.79 (1 H, m, 3-H), 3.98

(0.11 g, 0.52 mmol) and Et₃N (0.07 mL, 0.71 mmol) were (1 H, m, 6-H), 4.1 (0.6 H, m, 8-H), 4.25 (0.4 H, m, 8-H) and

added to the secondary amine 38 (0.15 g, 0.47 mmol) in DCM 9.78 (1 H, m, 1-H); m/z (CI) 328 (M⁺+ 1, 3%), 272 (25) and 228

(3 mL) at room temperature and the mixture stirred for 16 h. (100).

Water (5 mL) was added and the aqueous layer was extracted

M^ETHYL(2R,3R,6S,8R)-8-(N-TERT-BUTOXYCARBONYL-N-METHYLAMINO)-

with DCM (3 × 5 mL). The organic extracts were washed with 3,6-^EPOXY-2-METHYLUNDECANOATE (43). 2-Methylbut-2-ene (2 M in

water (10 mL) and brine (10 mL) then dried (MgSO₄) and con- THF, 3.68 mmol, 1.84 mL), sodium chlorite (80% tech. grade,

centrated under reduced pressure. Chromatography of the 0.21 g, 2.30 mmol) and sodium dihydrogen phosphate (0.55 g,

residue using light petroleum : ether (gradient elution 5 : 1 to 4.60 mmol) were added to the aldehyde 41 (0.12 g,

2 : 1) gave the title compound 39 (0.176 g, 90%) as a colourless 0.367 mmol) in BuOH : H₂O (1 : 1, 9 mL) and the mixture was

oil, a 40 : 60 mixture of rotamers, R_f= 0.36 (2 : 1 light stirred for 2 h at room temperature. Brine (3 mL) was added

petroleum : ether); [α]_D²⁶−8.2 (c 0.54 in CHCl₃) (Found: M⁺+ H, and the mixture diluted with EtOAc (3 mL). The aqueous layer

420.3115. C₂₅H₄₂NO₄requires M, 420.3114); ν_max/cm⁻¹1695, was extracted with EtOAc (3 × 10 mL) and the organic extracts

1455, 1399, 1365, 1338, 1250, 1150, 1071, 875, 771 and 735; δ_Hwere dried (MgSO₄) and concentrated under reduced pressure

(300 MHz, CDCl₃) 0.80–1.02 (6 H, m, 1-CH₃, 11-H₃), 1.10–1.70 to leave the acid 42 as an oil, a 60 : 40 mixture of rotamers

(7 H, m), 1.48 [9 H, s, C(CH₃)₃], 1.80–2.13 (4 H, m), 2.66 (1.2 H, (Found: M⁺+ H, 344.2439. C₁₈H₃₄NO₅requires M, 344.2437);

s, NCH₃), 2.70 (1.8 H, s, NCH₃), 3.40 (1 H, m, 1-H), 3.66 (1 H, ν_max/cm⁻¹1736, 1691, 1461, 1399, 1366, 1154, 1062, 939, 872

dd, J 9.2, 4.8, 1-H′), 3.68–3.81 (2 H, m, 2-H, 6-H), 4.10 (0.6 H, and 770; δ_H(CDCl₃, 300 MHz) 0.86 (3 H, t, J 7, 11-H₃), 1.13 (3

m, 8-H), 4.24 (0.4 H, m, 8-H), 4.55 (2 H, s, PhCH₂) and H, d, J 7.1, 2-CH₃), 1.16–1.70 (7 H, m), 1.40 [9 H, s, C(CH₃)₃],

7.30–7.40 (5 H, m, ArH); m/z (CI) 420 (M⁺+ 1, 71%), 364 (10) 1.74–2.1 (3 H, m), 2.47 (1 H, m, 2-H), 2.58 (1.2 H, s, NCH₃),

and 320 (100).

2.61 (1.8 H, s, NCH₃), 3.79 (1 H, m, 6-H), 3.95 (1 H, q, J 6.6, 3-

(2S,3R,6S,8R)-8-(N-^TERT-BUTOXYCARBONYL-N-METHYLAMINO)-3,6- H), 4.03 (0.6 H, m, 8-H) and 4.19 (0.4 H, m, 8-H); m/z (CI) 344

EPOXY-2-METHYLUNDECAN-1-OL (40). The benzyl ether 39 (410 mg) (M⁺+ 1, 5%), 288 (20) and 244 (100).

and Pd/C (10%, cat.) in ethanol (10 mL) was stirred under an

This acid 42 was azeotroped with benzene then dissolved in

atmosphere of hydrogen for 16 h. The catalyst was removed by benzene : methanol (4 : 1, 8 mL). (Trimethylsilyl)diazomethane

filtration through Celite® and the filtrate concentrated under (1 M in hexanes, 0.734 mmol, 0.37 mL) was added slowly at

reduced pressure. The residue was azeotroped with benzene to room temperature After 1.5 h, the mixture was concentrated

give the title compound 40 (286 mg, 89%) as an oil, a under reduced pressure and chromatography of the residue

40 : 60 mixture of rotamers, [α]²_D⁶+4.6 (c 1.1 in CHCl₃) (Found: using 3 : 1 light petroleum : ether gave the title compound 43

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9721

Paper

(98 mg, 75%) as an oil, a 60 : 40 mixture of rotamers, R_f= 0.46 (2.87 g, 7.53 mmol) in THF (5 mL) cooled to 0 °C was added.

(1 : 1 light petroleum : ether); [α]²_D⁶−12.8 (c 1.0 in CHCl₃) The mixture was stirred for 1 h at −78 °C then saturated

(Found: M⁺+ H, 358.2595. C₁₉H₃₆NO₅requires M, 358.2593); aqueous ammonium chloride was added. The mixture was

ν_max/cm⁻¹1741, 1691, 1458, 1398, 1365, 1340, 1256, 1150, allowed to warm to room temperature and was then stirred for

1063 and 769; δ_H(300 MHz, CDCl₃) 0.93 (3 H, t, J 7.1, 11-H₃), 30 min. Ether was added and the aqueous layer was extracted

1.15 (3 H, d, J 7.0, 2-CH₃), 1.21–1.70 (8 H, m), 1.46 [9 H, s, with more ether. The organic extracts were washed with water

C(CH₃)₃], 1.81–2.16 (2 H, m), 2.55 (1 H, m, 2-H), 2.64 (1.2 H, s, and brine then dried (MgSO₄) and concentrated under

NCH₃), 2.68 (1.8 H, s, NCH₃), 3.73 (3 H, s, OCH₃), 3.79 (1 H, reduced pressure. Chromatography using light petroleum :

m), 4.05 (1.4 H, m) and 4.21 (0.6 H, m, 8-H); δ_C(75 MHz, ether (gradient elution 3 : 1 to 1 : 1) gave a mixture of the title

CDCl₃) 13.2, 13.4, 13.6, 13.8, 19.0, 19.2, 28.2, 28.3, 28.3, 30.8, compounds 46 and 48 (2.66 g, 63%) as a colourless liquid

30.9, 34.9, 35.1, 38.2, 38.7, 45.1, 45.3, 51.5, 52.3, 77.0, 77.4, (Found: M⁺

78.8, 79.1, 80.1, 80.2, 155.9 and 175.1; m/z (CI) 358 (M⁺+ 1, 577.3311); ν_max/cm⁻¹3520, 1752, 1462, 1380, 1336, 1152, 1092,

48%) and 258 (100). 922, 816, 759 and 719; δ_H(CDCl₃, 300 MHz) 0.84 (3 H, m, 13-

+ NH₄, 577.3301. C₃₁H₄₉N₂O₆S requires M,

M^ETHYL(2R,3R,6S,8R)-3,6-EPOXY-2-METHYL-8-(METHYLAMINO)UNDE- H₃), 1.02 (3 H, d, J 7, 4-CH₃), 1.05–1.80 (8 H, m), 1.35 (3 H, d, J

^CANOATE(44).⁵Concentrated aqueous hydrogen chloride (few 7, 2-CH₃), 2.0–2.2 (3 H, m), 2.24 (6 H, s, 2 × ArCH₃), 2.44 (3 H,

drops) was added to the carbamate 43 (84 mg) in ethyl acetate s, ArCH₃), 2.7 (3 H, s, NCH₃), 3.0 (1 H, dq, J 10. 7, 2-H), 3.15 (1

(2 mL) and the mixture stirred for 15 h at room temperature. H, d, J 4.2, OH), 3.75–4.1 (3 H, m), 4.35 (1 H, ddd, J 10, 4, 2, 3-

Aqueous sodium bicarbonate and ethyl acetate were added H), 7.09 (3 H, s, ArH) and 7.3 and 7.7 (each 2 H, d, J 8.3, ArH);

and the aqueous layer extracted with ethyl acetate. The organic m/z (CI) 577 (M⁺+ 18, 90%) and 86 (100). The second fraction

extracts were dried (MgSO₄) and concentrated under reduced contained the title compound 50 (289 mg, 7%) as a white solid,

pressure. Chromatography of the residue using 1 : 1 light [α]²_D⁵+1.96 (c 0.82 in CHCl₃) (Found: M⁺+ NH₄, 577.3318.

petroleum : ether (with 1% Et₃N) gave the title compound 44 C₃₁H₄₉N₂O₆S requires M, 577.3311); ν_max/cm⁻¹3438, 1748,

(29 mg, 48%), as a colourless oil, [α]²_D²−26 (c 0.75 in CHCl₃) 1598, 1461, 1337, 1153, 1090, 1056, 927, 816 and 758; δ_H

lit.^5k[α]_D²⁰−28.2 (c 0.85 in CHCl₃); ν_max/cm⁻¹3357, 1739, 1461, (CDCl₃, 300 MHz) 0.84–1.04 (3 H, m, 13-H₃), 1.14 (3 H, d, J 7.1,

1377, 1260, 1198, 1162, 1062, 854 and 760; δ_H(CDCl₃, 4-CH₃), 1.15–2.20 (10 H, m), 1.58 (3 H, d, J 7, 2-CH₃), 1.95 (6 H,

300 MHz) 0.90 (3 H, t, J 6.7, 11-H₃), 1.10 (3 H, d, J 7, 2-CH₃), s, 2 × ArCH₃), 2.45 (3 H, s, ArCH₃), 2.71 (1 H, m, 4-H), 2.71 (3

1.20–1.70 (7 H, m), 1.90–2.10 (3 H, m), 2.34 (3 H, s, NCH₃), H, s, NCH₃), 3.05 (1 H, dq, J 9.5 and 7.5, 2-H), 3.26 (1 H, d, J

2.50 (2 H, m, 2-H and 8-H), 3.68 (3 H, s, OCH₃) and 3.96 (2 H, 3.3, OH), 3.74–4.14 (3 H, m), 4.24 (1 H, dt, J 9.5 and 2.8, 3-H),

m, 3-H and 6-H); δ_C(CDCl₃, 75 MHz) 13.3, 14.3, 18.7, 28.3, 7.09 (3 H, s, ArH), 7.32 and 7.73 (each 2 H, d, J 8.1, ArH); δ_C

31.8, 33.4, 36.0, 40.0, 45.4, 51.5, 58.4, 78.8, 80.8 and 175.4.

(CDCl₃, 75 MHz) 11.4, 13.7, 14.9, 16.4, 19.6, 21.4, 27.6, 29.0,

M^ETHYL(2R,3R,6S,8R)-8-(DIMETHYLAMINO)-3,6-EPOXY-2-METHYLUNDE- 31.1, 34.3, 37.7, 40.0, 43.1, 55.0, 71.7, 77.0, 82.6, 125.7, 127.0,

^CANOATE(45 ).⁵Formalin (85 μL, 1.13 mmol) and NaBH₃CN 127.1, 128.6, 129.4, 130.0 and 173.2; m/z (EI) 560 (M⁺+ 1, 2%),

(36 mg, 0.564 mmol) were added to the secondary amine 44 438 (10), 382 (70) and 240 (100).

(29 mg, 0.113 mmol) in acetonitrile (1.5 mL) and the solution

2,6-D^{IMETHYLPHENYL}(2R,3R,4R,5R,8S,10R)- AND (2S,3S,4R,5R,8S,10R)-

stirred for 1 h at room temperature. Acetic acid (12 mL) was 3-^TERT-BUTYLDIMETHYLSILYLOXY-2,4-DIMETHYL-5,8-EPOXY-10-[N-METHYL-

added and the solution stirred for 1.5 h. After concentration N-(^TOLUENE-4-SULFONYL)AMINO]TRIDECANOATES (47) AND (49). 2,6-Luti-

under reduced pressure, chromatography using 1 : 1 light dine (1.34 mL, 11.53 mmol) and tert-butyldimethylsilyl tri-

petroleum : ether (with 1% Et₃N) gave the title compound 45 fluoromethylsulfonate (1.76 mL, 7.69 mmol) were added to a

(16 mg, 52%), as a colourless oil, [α]²_D²−19.2 (c 0.375 in CHCl₃) mixture of the aldol products 46 and 48 (2.15 g, 3.84 mmol) in

lit.^5k[α]_D²⁰−23.9 (c 0.715 in CHCl₃); ν_max/cm⁻¹1740, 1461, DCM (40 mL) at room temperature and the solution stirred for

1376, 1260, 1197, 1162, 1062, 890 and 855; δ_H(CDCl₃, 16 h. Water was added and the aqueous layer extracted with

300 MHz) 0.90 (3 H, t, J 6.9, 11-H₃), 1.11 (3 H, d, J 7, 2-CH₃), DCM. The organic extracts were washed with water and brine

1.18–1.51 (6 H, m), 1.63 and 1.78 (each 1 H, m), 1.98 (2 H, m), then dried (MgSO₄) and concentrated under reduced pressure.

2.20 [6 H, s, N(CH₃)₂], 2.52 (2 H, m, 2-H and 8-H), 3.69 (3 H, s, Chromatography of the residue using 7 : 1 light petroleum :

OCH₃), 3.93 (1 H, quin, J 6.5, 6-H) and 4.02 (1 H, q, J 6.7, 3-H); ether gave the title compound 49 (1.71 g, 66%) as a colourless

δ_C(CDCl₃, 75 MHz) 13.3, 14.2, 20.1, 28.4, 31.1, 31.7, 35.5, 40.1, liquid, [α]²_D⁵−2.67 (c 1.2 in CHCl₃) (Found: M⁺, 673.3827.

45.5, 51.5, 60.6, 77.5, 80.1 and 175.4.

C₃₇H₅₉NO₆SSi requires M, 673.3832); ν_max/cm⁻¹1755, 1466,

2,6-D^{IMETHYLPHENYL}(2R,3R,4S,5R,8S,10R)-, (2S,3S,4S,5R,8S,10R)- 1341, 1256, 1154, 1092, 1049, 934, 836 and 774; δ_H(CDCl₃,

AND (2R,3S,4S,5R,8S,10R)-2,4-DIMETHYL-5,8-EPOXY-3-HYDROXY-10-[N- 500 MHz) 0.08 and 0.1 (each 3 H, s, SiCH₃), 0.81 (3 H, t, J 7,

METHYL-N-(TOLUENE-4-SULFONYL)AMINO]TRIDECANOATES (46), (48) AND 13-H₃), 0.92 [12 H, m, SiC(CH₃)₃and 4-CH₃], 1.05–1.20 (3 H,

(50). n-Butyllithium (2.05 M in hexanes, 16.3 mL, 33.4 mmol) m), 1.25–1.45 (4 H, m), 1.38 (3 H, d, J 7.2, 2-CH₃), 1.64, 1.82,

was added to di-isopropylamine (3.37 mL, 33.4 mmol) in THF 1.92 and 2.02 (each 1 H, m), 2.16 (6 H, s, 2 × ArCH₃), 2.40 (3 H,

(15 mL) and the mixture cooled to 0 °C. After 15 min, the sol- s, ArCH₃), 2.66 (3 H, s, NCH₃), 3.04 (1 H, dq, J 5.0, 6.5, 2-H),

ution was cooled down to −78 °C and 2,6-dimethylphenyl pro- 3.54 (1 H, dt, J 5.0 and 6.8, 5-H), 3.66 and 3.95 (each 1 H, quin,

pionate (5.95 g, 33.4 mmol) in THF (5 mL) was added. The J 7.2, 8-H or 10-H), 4.54 (1 H, dd, J 6 and 2, 3-H), 7.03 (3 H, m,

solution was stirred for 1 h at −78 °C then the aldehyde 37 ArH) and 7.25 and 7.68 (each 2 H, d, J 8.1, ArH); δ_C(CDCl₃,

9722 | Org. Biomol. Chem., 2012, 10, 9709–9733

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Organic & Biomolecular Chemistry

125 MHz) −5.0, −4.0, 10.6, 13.6, 13.8, 16.8, 18.5, 19.6, 21.4, requires M, 556.3492); ν_max/cm⁻¹3451, 1462, 1339, 1254, 1153,

26.2, 27.6, 29.7, 31.0, 34.0, 38.1, 41.9, 46.1, 54.7, 71.8, 75.7, 1089, 1038, 837 and 773; δ_H(CDCl₃, 500 MHz) 0.08 and 0.12

80.2, 125.6, 127.1, 128.5, 129.4, 130.2, 137.3, 142.8, 148.2 and (each 3 H, s, SiCH₃), 0.83 (3 H, t, J 7, 13-H₃), 0.86 (3 H, d, J 7,

172.1; m/z (CI) 691 (M⁺+ 18, 2%), 674 (M⁺+ 1, 1) and 86 (100). 4-CH₃), 0.88 (3 H, d, J 7, 2-CH₃), 0.92 [9 H, s, SiC(CH₃)₃], 1.12

The second fraction contained the title compound 47 (0.44 g, (1 H, m), 1.2 (2 H, m), 1.34 (1 H, m), 1.42 (3 H, m), 1.6 and

17%) as a colourless oil, [α]²_D⁵−4.83 (c 0.91 in CHCl₃) (Found: 1.92 (each 2 H, m), 2.04 (1 H, m), 2.42 (3 H, s, ArCH₃), 2.65

M⁺+ NH₄, 691.4173. C₃₇H₆₃N₂O₆SSi requires M, 691.4176); (3 H, s, NCH₃), 2.86 (1 H, dd, J 7.5 and 3.7, OH, D₂O exchange-

ν_max/cm⁻¹1755, 1467, 1339, 1256, 1156, 1094, 1051, 931, 837 able), 3.45–3.62 (3 H, m, 1-H₂and 5-H), 3.77 and 4.01

and 773; δ_H(CDCl₃, 500 MHz) 0.09 and 0.12 (each 3 H, s, (each 1 H, m, 8-H or 10-H), 4.12 (1 H, dd, J 6.2 and 1.8, 3-H),

SiCH₃), 0.84 (3 H, t, J 7, 13-H₃), 0.91 [9 H, m, SiC(CH₃)₃], 0.93 7.28 and 7.70 (each 2 H, d, J 8.1, ArH); δ_C(CDCl₃, 125 MHz)

(3 H, d, J 7, 4-CH₃), 1.10–1.31 (3 H, m), 1.35 (2 H, m), 1.41 (3 −4.6, −4.2, 11.0, 13.0, 13.8, 18.3, 19.7, 21.5, 26.1, 27.7, 30.1,

H, d, J 7, 2-CH₃), 1.47, 1.56, 1.68 and 1.88 (each 1 H, m), 2.06 30.8, 33.8, 38.2, 40.8, 41.4, 54.6, 65.8, 73.9, 75.6, 81.5, 127.2,

(2 H, m), 2.18 (6 H, s, 2 × ArCH₃), 2.41 (3 H, s, ArCH₃), 2.68 (3 129.4, 137.2 and 142.9; m/z (CI) 556 (M⁺+ 1, 50%) and

H, s, NCH₃), 3.08 (1 H, dq, J 5.1, 7.9, 2-H), 3.76 (1 H, quin, J 86 (100).

7.5), 3.98 (2 H, m), 4.19 (1 H, dd, J 6.0 and 4.5, 3-H), 7.05 (3 H,

m, ArH) and 7.27 and 7.7 (each 2 H, d, J 8.1, ArH); δ_C(CDCl₃, ^CARBONYL)-10-[N-METHYL-N-(TOLUENE-4-SULFONYL)AMINO]TRIDECANE (54).

125 MHz) −4.6, −4.2, 10.7, 13.7, 13.8, 16.8, 18.3, 19.7, 21.5, Tetrabutylammonium fluoride (1 in THF, 270 μL,

(2R,3R,4R,5R,8S,10R)-2,4-D^IMETHYL-5,8-EPOXY-1,3-(1,3-BIS-EPOXY-

26.0, 27.7, 27.9, 31.3, 34.0, 38.0, 42.5, 44.1, 54.8, 75.2, 75.9, 0.27 mmol) was added to the silyl ether 52 (75 mg,

79.6, 125.6, 127.1, 128.6, 129.4, 130.2, 137.3, 142.8, 148.3 and 0.135 mmol) in THF (1 mL) at room temperature and the sol-

172.2; m/z (EI) 674 (M⁺+ 1, 20%), 616 and 552 (100).

ution was stirred for 2 h. After concentration under reduced

2,6-D^{IMETHYLPHENYL}(2R,3S,4R,5R,8S,10R)-3-TERT-BUTYLDIMETHYL- pressure, water and DCM were added and the aqueous phase

^SILYLOXY-2,4-DIMETHYL-5,8-EPOXY-10-[N-METHYL-N-(TOLUENE-4-SULFONYL) was extracted with DCM. The organic extracts were washed

AMINO]TRIDECANOATE (51). Following the procedure used to with water and brine then dried (MgSO₄) and concentrated

prepare the silyl ethers 47 and 49, the aldol product 50 (40 mg, under reduced pressure. Chromatography of the residue using

0.71 mmol) gave the title compound 51 (34 mg, 70%) as a col- 1 : 2 light petroleum : ether gave the diol 53 (53 mg, 89%) as a

ourless oil (Found: M⁺+ NH₄, 691.4180. C₃₇H₆₃N₂O₆SSi colourless liquid, [α]²_D¹−11.2 (c 0.3 in CHCl₃); ν_max/cm⁻¹3432,

requires M, 691.4176); ν_max/cm⁻¹1750, 1464, 1339, 1256, 1154, 1598, 1461, 1383, 1335, 1154, 1090, 1037, 923, 816 and 758; δ_H

1091, 1056, 931, 836 and 773; δ_H(CDCl₃, 500 MHz) 0.1 and (CDCl₃, 300 MHz) 0.76 (6 H, m, 13-H₃and 2- or 4-CH₃), 0.97 (3

0.15 (each 3 H, s, SiCH₃), 0.82 (3 H, t, J 7, 13-H₃), 0.94 [12 H, H, d, J 7, 4- or 2-CH₃), 1.04–1.3 (4 H, m), 1.36–1.76 (5 H, m),

m, SiC(CH₃)₃and 4-CH₃], 1.06–1.41 (7 H, m), 1.43 (3 H, d, J 7, 1.9 (2 H, m), 2.1 (1 H, m), 2.39 (3 H, s, ArCH₃), 2.63 (3 H, s,

2-CH₃), 1.58 (1 H, m), 1.69 (1 H, m, 4-H), 1.98 (2 H, m), 2.16 (6 NCH₃), 3.4–4.0 (8 H, m) and 7.25 and 7.65 (each 2 H, d, J 8.2,

H, s, 2 × ArCH₃), 2.33 (3 H, s, ArCH₃), 2.64 (3 H, s, NCH₃), 2.94 ArH); δ_C(CDCl₃, 75 MHz) 10.7, 13.4, 13.7, 19.6, 21.4, 27.5,

(1 H, dq, J 7.9, 6.9, 2-H), 3.48 (1 H, m, 5-H), 3.64 and 3.99 29.2, 31.1, 34.3, 37.0, 37.8, 39.2, 55.0, 69.2, 76.7, 77.0, 82.7,

(each 1 H, quin, J 7.0, 8-H or 10-H), 4.43 (1 H, dd, J 9.0, 1.5, 3- 127.0, 129.4, 137.5 and 142.9.

H), 7.05 (3 H, m, ArH) and 7.2 and 7.68 (each 2 H, d, J 8.1,

Carbonyl di-imidazole (97 mg, 0.6 mmol) was added to the

ArH); δ_C(CDCl₃, 125 MHz) −4.5, −3.7, 9.6, 13.9, 16.3, 16.7, diol 53 (53 mg, 0.12 mmol) in dry benzene (5 mL) and the

18.6, 19.6, 21.4, 26.2, 27.6, 30.5, 30.9, 33.9, 37.9, 43.9, 44.9, solution was heated under reflux for 16 h. After concentration

54.8, 72.4, 75.7, 79.3, 125.7, 127.1, 128.6, 129.4, 130.2, 137.3, under reduced pressure, chromatography of the residue using

142.7, 148.1 and 173.1; m/z (CI) 691 (M⁺+ 18, 50%), 674 (M⁺+ 1 : 2 light petroleum : ether gave the title compound 54 (49 mg,

1, 15) and 86 (100).

87%), as a colourless liquid, ν_max/cm⁻¹1752, 1667, 1461, 1405,

(2R,3R,4R,5R,8S,10R)-3-^TERT-BUTYLDIMETHYLSILYLOXY-2,4-DIMETHYL- 1334, 1211, 1152, 1123, 1088, 924 and 761; δ_H(CDCl₃,

5,8-^EPOXY-10-[N-METHYL-N-(TOLUENE-4-SULFONYL)AMINO]TRIDECAN-1-OL 500 MHz) 0.84 (3 H, t, J 6.8, H-13), 0.92 (3 H, d, J 6.6, 4-CH₃),

(52). Di-isobutylaluminium hydride (1 M in DCM, 16.5 mL, 0.98 (3 H, d, J 6.6, 2-CH₃), 1.19 (3 H, m), 1.38–1.62 (5 H, m),

16.5 mmol) was added slowly to the ester 49 (4.45 g, 1.75 (1 H, m, 4-H), 2.04 (2 H, m), 2.19 (1 H, m, 2-H), 2.43 (3 H,

6.61 mmol) in DCM (55 mL) at −78 °C and the solution was s, ArCH₃), 2.64 (3 H, s, NCH₃), 3.84 (2 H, m), 4.04 (1 H, t, J 11,

stirred for 30 min at −78 °C then warmed to room temperature 1-H), 4.08 (1 H, m), 4.28 (1 H, dd, J 10.7 and 4.8, 1-H′), 4.64 (1

over a period of 1 h. The solution was then cooled to −78 °C H, dd, J 10.6 and 1.5, 3-H), 7.28 and 7.68 (each 2 H, d, J 8.2,

and MeOH (ca. 3 mL) and saturated aqueous ammonium ArH); δ_C(CDCl₃, 75 MHz) 8.5, 11.2, 13.6, 19.3, 21.2, 27.3, 27.9,

chloride (ca. 20 mL) were added. The mixture was allowed to 29.5, 30.8, 33.4, 39.0, 39.8, 54.2, 72.0, 75.6, 78.5, 83.8, 126.9,

warm to room temperature and was stirred for a further 129.1, 137.0, 142.7 and 150.0.

45 min then filtered through Celite®, washed with water and

M^ETHYL(4S,5R,8S,10R,2E)-10-[N-METHYL-N-(TOLUENE-4-SULFONYL)-

brine then dried (MgSO₄). After concentration under reduced AMINO]-5,8-EPOXY-4-METHYLTRIDEC-2-ENOATE (55). (Methoxycarbonyl-

pressure, chromatography of the residue using light methylene)triphenylphosphorane (188 mg, 0.564 mmol) was

petroleum : ether (gradient elution 4 : 1 to 2 : 1) gave the title added to freshly prepared aldehyde 37 (from Swern oxidation

compound 52 (2.93 g, 80%) as a colourless liquid, [α]²_D³−19.1 of 144 mg, 0.376 mmol, of alcohol 36) in DCM (1.5 mL) and

(c 1.05 in CHCl₃) (Found: M⁺+ H, 556.3490. C₂₉H₅₄NO₅SSi the mixture stirred for 48 h. After concentration under reduced

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9723

Paper

pressure, chromatography using 3 : 1 light petroleum : ether) gave the title compound 57 (61 mg, 70%) as a colourless liquid,

gave the title compound 55 (133 mg, 81% from 34) as colourless 57 : 58 H, 426.2316.

95 : 5 (¹H NMR) (Found: M⁺

oil (Found: M⁺+ H, 438.2318. C₂₃H₃₆NO₅S requires M, C₂₂H₃₆NO₅S requires M, 426.2314); ν_max/cm⁻¹3425, 1598,

438.2314); ν_max/cm⁻¹1723, 1656, 1598, 1459, 1437, 1338, 1274, 1462, 1380, 1335, 1151, 1089, 1058, 927, 898, 816, 759 and 718;

1153, 1090, 1055, 1040, 989, 928, 817 and 719; δ_H(CDCl₃, δ_H(CDCl₃, 500 MHz) 0.85 (3 H, t, J 7, 13-H₃), 1.02 (3 H, d, J 6.8,

300 MHz) 0.85 (3 H, t, J 7, 13-H₃), 1.08 (3 H, d, J 6.9, 4-CH₃), 4-CH₃), 1.10–1.30 (4 H, m), 1.35–1.60 (5 H, m), 1.72 (1 H, br. s,

1.12–1.52 (6 H, m), 1.58, 1.70, 1.92 and 2.08 (each 1 H, m), OH), 1.98 and 2.06 (each 1 H, m), 2.42 (3 H, s, ArCH₃), 2.64 (3

2.44 (4 H, m, ArCH₃and 4-H), 2.70 (3 H, s, NCH₃), 3.70 (1 H, q, H, s, NCH₃), 2.87 (1 H, dd, J 7.7 and 2.3, 3-H), 3.12 (1 H, m, 2-

J 7, 5-H), 3.76 (3 H, s, OCH₃), 3.81 and 3.98 (each 1 H, m, 8-H H), 3.65 (1 H, q, J 7.0, 5-H), 3.72 (1 H, dd, J 12.4 and 4.3, 1-H),

or 10-H), 5.9 (1 H, dd, J 15.8 and 1.1, 2-H), 7.0 (1 H, dd, J 15.8 3.82 (1 H, quin, J 6.6, 8-H), 3.87 (1 H, dd, J 12.4 and 3.4, 1-H′),

and 7.7, 3-H) and 7.31 and 7.72 (each 2 H, d, J 8.2, ArH); δ_C4.10 (1 H, quin, J 6.9, 10-H) and 7.4 and 7.7 (each 2 H, d, J 8.2,

(CDCl₃, 75 MHz) 13.7, 15.4, 19.6, 21.4, 27.6, 28.6, 30.9, 34.1, ArH); δ_C(CDCl₃, 100 MHz) 13.8, 15.2, 19.6, 21.4, 27.5, 29.4,

37.9, 41.6, 51.3, 54.7, 76.5, 81.7, 120.7, 127.1, 129.4, 137.3, 30.9, 33.5, 38.7, 41.9, 54.6, 59.0, 62.2, 65.8, 76.1, 81.2, 127.1,

142.8, 151.3 and 167.0; m/z (EI) 438 (M⁺+ 1, 4%), 394 (5), 282 129.3, 137.2 and 142.9; m/z (EI) 426 (M⁺+ 1, 8%), 240 (80) and

(15), 240 (85) and 86 (100).

(4S,5R,8S,10R,2E)-10-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]-

86 (100).

Methyllithium (1.6 M in ether, 1.42 mL, 2.27 mmol) was

5,8-^EPOXY-4-METHYLTRIDEC-2-EN-1-OL

(56). Di-isobutylaluminium added to a suspension of copper(^I) iodide (230 mg, 1.2 mmol)

hydride (1 M in hexane, 0.99 μL, 0.99 mmol) was added to the in ether (3.5 mL) at −10 °C. After 30 min, epoxide 57 (34 mg,

ester 55 (122 mg, 0.279 mmol) in DCM (1 mL) at −78 °C. The 0.08 mmol) in ether (0.5 mL) was added slowly and the

solution was stirred for 30 min at −78 °C and at room tempera- mixture was stirred for 5 h at −10 °C. The mixture was then

ture for 90 min. It was then cooled to −78 °C and methanol poured onto a mixture of saturated aqueous ammonium chlor-

and aqueous sodium bicarbonate were added. After being ide and aqueous ammonium hydroxide and the ensuing

allowed to warm to room temperature, the mixture was stirred mixture was stirred for 10 min. The aqueous layer was

for another 30 min and filtered through Celite®. The organic extracted with DCM and the organic extracts were washed with

layer was washed with water and brine, dried (MgSO₄) and con- brine, dried (MgSO₄) and concentrated under reduced

centrated under reduced pressure. Chromatography of the pressure. Chromatography of the residue using light

residue using 1 : 1 light petroleum : ether gave the title com- petroleum : ether (gradient elution 1 : 1 to 1 : 2) gave the diol

pound 56 (84 mg, 74%) as a colourless liquid (Found: M⁺+ H, 53 (20 mg, 57%) as a colourless liquid with spectroscopic data

410.2361. C₂₂H₃₆NO₄S requires M, 410.2365); ν _max/cm⁻¹3402, identical to those of the sample prepared earlier by desilyla-

1598, 1461, 1336, 1154, 1091, 1051 and 816; δ_H(CDCl₃, tion of the silyl ether 52.

300 MHz) 0.86 (3 H, t, J 7, 13-H₃), 1.04 (3 H, d, J 6.9, 4-CH₃),

(2R,3R,4R,5R,8S,10R)-10-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]-

1.05–2.00 (9 H, m), 2.06 and 2.30 (each 1 H, m), 2.45 (3 H, s, 2,3;5,8-^BIS-EPOXY-4-METHYLTRIDECAN-1-OL (58). Following the pro-

ArCH₃), 2.69 (3 H, s, NCH₃), 3.66 (1 H, q, J 7.1, 5-H), 3.82 (1 H, cedure outlined for the synthesis of epoxide 57 but using

quin, J 7.0, 8-H), 4.04 (1 H, quin, J 7.0, 10-H), 4.14 (2 H, m, 1- diethyl ^D-(−)-tartrate, the alkenol 56 (78 mg, 0.19 mmol) gave

H₂), 5.75 (2 H, m, 2-H and 3-H) and 7.31 and 7.74 (each 2 H, d, the title compound 58 (81 mg, 80%) as a colourless oil contain-

J 8.2, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 16.3, 19.6, 21.4, 27.6, ing only traces, <2%, of 57 (¹H NMR) (Found: M⁺+ H,

28.5, 31.1, 34.0, 38.2, 41.5, 54.7, 63.7, 76.2, 82.7, 127.1, 129.0, 426.2312. C₂₂H₃₆NO₅S requires M, 426.2314); δ_H(CDCl₃,

129.3, 135.1, 137.3 and 142.7; m/z (CI) 427 (M⁺+ 18, 97%), 410 500 MHz) 0.84 (3 H, t, J 7, 13-H₃), 0.94 (3 H, d, J 6.8, 4-CH₃),

(M⁺+ 1, 100) and 392 (85).

1.10–1.26 (3 H, m), 1.34, 1.42 and 1.49 (each 1 H, m), 1.69 and

(2S,3S,4R,5R,8S,10R)-10-[N-M^ETHYL-N-(TOLUENE-4-SULFONYL)AMINO]- 1.92 (each 2 H, m), 2.08 (1 H, m), 2.42 (3 H, s, ArCH₃), 2.64 (3

2,3;5,8-^BIS-EPOXY-4-METHYLTRIDECAN-1-OL (57). The alkenol 56 H, s, NCH₃), 3.02 (1 H, m, 2-H), 3.06 (1 H, dd, J 6.8 and 2.3,

(84 mg, 0.205 mmol) and diethyl ^L-(+)-tartrate (105 mg, 3-H), 3.68 (1 H, ddd, J 12.1, 7.2 and 4.5, 1-H), 3.72 (1 H, q, J

0.513 mmol) in dry DCM (1.5 mL) were added to titanium(^IV) 7.0, 5-H), 3.84 (1 H, quin, J 6.8), 3.89 (1 H, ddd, J 12.5, 6.1, 3.0,

isopropoxide (146 mg, 0.513 mmol) in DCM (1 mL) at −23 °C. 1-H′), 4.0 (1 H, quin, J 7.1) and 7.4 and 7.7 (each 2 H, d, J 8.2,

Anhydrous tert-butyl hydroperoxide (4.5 M in toluene, 0.32 mL, ArH); δ_C(CDCl₃, 125 MHz) 12.5, 13.8, 19.7, 21.5, 27.7, 28.7,

1.43 mmol) was added slowly and the mixture was stirred at 31.0, 34.2, 38.2, 39.6, 54.9, 55.8, 57.6, 62.0, 76.5, 81.3, 127.2,

−23 °C for 2 h. Aqueous tartaric acid (2 mL) was added and 129.4, 137.4 and 142.8; m/z (CI), 426 (M⁺+ 1, 50%), 272 (40)

the mixture stirred for 10 min. It was then warmed to room and 86 (100).

temperature and stirred for another 30 min. The aqueous layer

was extracted with DCM and the organic extracts concentrated ^BONYL)-10-[N-METHYL-N-(TOLUENE-4-SULFONYL)AMINO]TRIDECANE

(2S,3S,4R,5R,8S,10R)-2,4-D^IMETHYL-5,8-EPOXY-1,3-(BIS-1,3-EPOXYCAR-

(60).

under reduced pressure then diluted with ether and cooled to Following the procedure outlined for the synthesis of diol 53

0 °C. Aqueous sodium hydroxide (1 N, 1 mL) was added and from the epoxide 57, the epoxide 58 (58 mg, 0.136 mmol) gave

the mixture stirred for 1 h. The aqueous layer was extracted the diol 59 (45 mg, 72%) as a colourless oil (Found: M⁺+ H,

with DCM and the organic extracts dried (MgSO₄) then concen- 442.2631. C₂₃H₄₀NO₅S requires M, 442.2627); ν_max/cm⁻¹3440,

trated under reduced pressure. Chromatography of the residue 1598, 1462, 1335, 1154, 1089, 1040, 919, 816 and 732; δ_H

using light petroleum : ether (gradient elution 3 : 1 to 1 : 1) (CDCl₃, 300 MHz) 0.83 (6 H, m, 2- or 4-CH₃and 13-H₃),

9724 | Org. Biomol. Chem., 2012, 10, 9709–9733

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Organic & Biomolecular Chemistry

0.85–1.25 (4 H, m), 1.10 (3 H, d, J 7.0, 4- or 2-CH₃), 1.30–1.94 (6

(2R,6S,7R,8R,9R,10R,13S,15R,3Z)-1-B^ENZYLOXY-8-TERT-BUTYLDI-

H, m), 2.13 (2 H, m), 2.4 (3 H, s, ArCH₃), 2.69 (3 H, s, NCH₃), ^{METHYLSILYLOXY}-10,13-EPOXY-15-[N-METHYL-N-(TOLUENE-4-SULFONYL)-

3.34–3.60 and 3.75–3.90 (each 3 H, m) and 7.32 and 7.71 (each AMINO]-2,7,9-TRIMETHYLOCTADEC-3-EN-6-OL (63). Tin(IV) chloride (1

2 H, d, J 8.2, ArH); δ_C(CDCl₃, 75 MHz) 13.5, 13.7, 15.4, 19.6, M in DCM, 7.4 mL, 7.4 mmol) was added to the alkenylstan-

21.4, 27.6, 29.8, 30.9, 34.1, 35.2, 37.9, 42.4, 54.6, 64.5, 77.5, nane 3 (3.55 g, 7.4 mmol) in DCM (35 mL) at −78 °C. After

82.0, 85.3, 127.0, 129.4, 137.1 and 143.0; m/z (EI) 442 (M⁺+ 1, 5 min, a cooled (0 °C) solution of the aldehyde 62 (2.75 g,

20%), 240 (50) and 86 (100).

4.93 mmol) in DCM (35 mL) was added and the solution was

Reduction of the ester 47 (208 mg, 0.31 mmol) using stirred for 50 min at −78 °C. MeOH (2 mL) and aqueous

DIBAL-H (1 M in hexanes, 0.775 mL, 0.775 mmol) following sodium bicarbonate (25 mL) were added and the mixture was

the procedure outlined for the reduction of ester 49, gave the allowed to warm to room temperature and stirred for 1 h.

corresponding primary alcohol (65 mg, 38%); δ_H(CDCl₃, Water (50 mL) was added and the organic layer was washed

300 MHz) 0.03 and 0.06 (each 3 H, s, SiCH₃), 0.73 (3 H, t J 6.8, with water, dried (MgSO₄) and concentrated under reduced

13-H₃), 0.82 [9 H, s, C(CH₃)₃], 0.86 and 0.90 (each 3 H, d, J 7.2, pressure. Chromatography of the residue using light

2-CH₃or 4-CH₃), 1.00–2.05 (12 H, m), 2.34 (3 H, s, ArCH₃), 2.58 petroleum : ether (gradient elution 10 : 1 to 2 : 1) gave the title

(3 H, s, NCH₃), 2.94 (1 H, t, J 5.8, 3-H), 3.38–3.72 (4 H, m), compound 63 (3.04, 83%), [α]²_D¹−22.9 (c 1.15 in CHCl₃) (Found:

3.85–4.00 (2 H, m) and 7.19 and 7.61 (each 2 H, br. d, J 8.2, M⁺+ NH₄, 761.4980. C₄₂H₇₃N₂O₆SSi requires M, 761.4958);

ArH). Desilylation of this monosilyl ether using TBAF ν_max/cm⁻¹3477, 1457, 1340, 1253, 1153, 1093, 1042, 1005, 834

following the procedure outlined for the synthesis of diol and 774; δ_H(CDCl₃, 500 MHz) 0.06 and 0.13 (each 3 H, s,

53, gave the diol 59 (35 mg, 70%) with NMR spectra SiCH₃), 0.84 (3 H, t, J 7.2, 18-H₃), 0.86 (3 H, d, J 6.8, 9-CH₃),

identical to those of the sample of diol 59 prepared from the 0.91 [9 H, s, SiC(CH₃)₃], 0.93 (3 H, d, J 7, 7-CH₃), 0.95 (3 H, d, J

epoxide 58.

7, 2-CH₃), 1.10–1.28 (3 H, m), 1.30–1.44 (4 H, m), 1.50–1.60 (2

Following the procedure outlined for the synthesis of the H, m), 1.68, 1.90 and 2.0 (each 1 H, m), 2.14 and 2.37 (each 1

carbonate 54, the diol 59 (20 mg, 0.045 mmol) was converted H, m, 5-H), 2.38 (3 H, s, ArCH₃), 2.65 (3 H, s, NCH₃), 2.86 (1 H,

into the title compound 60 (14 mg, 67%) as a colourless liquid m, 2-H), 3.09 (1 H, br. s, OH), 3.26 (2 H, m, 1-H₂), 3.51 (1 H, m,

(Found: M⁺+ H, 468.2428. C₂₄H₃₈NO₆S requires M, 468.2420); 10-H), 3.7 (1 H, m, 13-H), 3.96–4.08 (2 H, m, 6-H and 15-H),

ν_max/cm⁻¹1754, 1463, 1404, 1335, 1212, 1152, 1122, 1087, 930, 4.15 (1 H, dd, J 5.9 and 1.9, 8-H), 4.5 (2 H, s, PhCH₂), 5.27 (1

817 and 759; δ_H(CDCl₃, 500 MHz) 0.93 (3 H, t, J 7, 13-H₃), 1.05 H, t, J 10.8, 3-H), 5.46 (1 H, dt, J 10.8 and 7.5, 4-H), 7.27 and

and 1.06 (each 3 H, d, J 7, 2-CH₃or 4-CH₃), 1.13–1.27 (3 H, m), 7.70 (each 2 H, d, J 8.2, ArH) and 7.32 (5 H, m, ArH); δ_C

1.33–1.44 (2 H, m), 1.45–1.53 (3 H, m), 1.90–2.04 (3 H, m), 2.42 (CDCl₃, 125 MHz) −4.3, −4.2, 10.0, 10.6, 13.7, 17.5, 18.4, 19.5,

(3 H, s, ArCH₃), 2.64 (3 H, s, NCH₃), 2.70 (1 H, m, 2-H), 21.4, 26.2, 27.6, 29.9, 31.0, 32.3, 33.7, 33.9, 38.3, 42.3, 42.4,

3.73–3.82 (2 H, m), 3.94 (1 H, t, J 10.5, 1-H), 4.07 (1 H, m), 4.19 54.6, 70.2, 72.8, 74.8, 75.0, 75.5, 80.7, 126.8, 127.1, 127.3,

(1 H, dd, J 10 and 1.8, 3-H), 4.26 (1 H, dd, J 10.5 and 4.3, 1-H′) 127.5, 128.2, 129.3, 134.7, 137.2, 138.5 and 142.6; m/z (CI), 762

and 7.3 and 7.7 (each 2 H, d, J 8.2, ArH); δ_C(CDCl₃, 125 MHz) (M⁺+ 19, 2%) and 86 (100).

12.4, 13.7, 14.0, 19.6, 21.4, 27.7, 29.1, 30.2, 30.6, 33.4, 38.9,

(2S,3S,4S,6S,7R,8S,9R,10R,13S,15R)-1-B^ENZYLOXY-8-TERT-BUTYLDI-

40.5, 54.5, 72.3, 76.1, 78.9, 88.4, 127.2, 129.4, 137.6, 142.9 and ^{METHYLSILYLOXY}-3,6;10,13-BIS-EPOXY-15-[N-METHYL-N-(TOLUENE-4-SULFO-

149.9; m/z (CI) 485 (M⁺+ 18, 15%), 468 (M⁺+ 1, 20) and 314 ^NYL)AMINO]-4-PHENYLSELENO-2,7,9-TRIMETHYLOCTADECANE (64). ZnCl₂

(100).

(ca. 500 mg) was added to the alkenol 63 (703 mg,

(2S,3S,4R,5R,8S,10R)-3-^TERT-BUTYLDIMETHYLSILYLOXY-2,4-DIMETHYL- 0.946 mmol) in DCM (16 mL). N-Phenylselenyl phthalimide

5,8-^EPOXY-10-[N-METHYL-N-(TOLUENE-4-SULFONYL)AMINO]TRIDECANAL (62). (430 mg, 1.42 mmol) in DCM (5 mL) was added over a period

Following the procedure outlined for the synthesis of aldehyde of 10 min and the mixture stirred for 2 h. Aqueous sodium

32, the alcohol 52 (3 g, 5.41 mmol) gave the aldehyde 62 bicarbonate was added and the aqueous layer was extracted

(2.84 g, 95%) as a light brown coloured liquid that was used with DCM. The organic extracts were washed with water and

immediately without chromatography, [α]²_D³−7.2 (c 0.89 in brine, dried (MgSO₄) and concentrated under reduced

CHCl₃) (Found: M⁺+ H, 554.3337. C₂₉H₅₂NO₅SSi M, 554.3335); pressure. Chromatography of the residue using 6 : 1 light

ν_max/cm⁻¹1727, 1463, 1341, 1254, 1153, 1090, 1041, 927, 838 petroleum : ether gave the title compound 64 (460 mg, 54%) as

and 776; δ_H(CDCl₃, 500 MHz) 0.07 (6 H, s, 2 × SiCH₃), 0.88 [15 a colourless liquid, [α]²_D¹+12.6 (c 1.27 in CHCl₃) (Found: M⁺+

H, m, SiC(CH₃)₃, 4-CH₃and 13-H₃], 1.08 (3 H, d, J 7, 2-CH₃), NH₄, 917.4434. C₄₈H₇₇N₂O₆SSi⁸⁰Se requires M, 917.4436); ν_max

1.16–1.46 (7 H, m), 1.50–1.65 and 1.90–2.05 (each 2 H, m), 2.42 cm⁻¹1598, 1578, 1495, 1472, 1456, 1382, 1341, 1250, 1207,

(3 H, s, ArCH₃), 2.55 (1 H, m, 2-H), 2.66 (3 H, s, NCH₃), 3.48 (1 1153, 1091, 1042, 933, 920, 877, 830, 814, 774, 734, 718, 693

H, m, 5-H), 3.71 (1 H, m, 8-H), 4.07 (1 H, m, 10-H), 4.4 (1 H, and 657; δ_H(CDCl₃, 500 MHz) 0.03 and 0.06 (each 3 H, s,

dd, J 6.2 and 2.3, 3-H), 7.28 and 7.70 (each 2 H, d, J 8.1, ArH) SiCH₃), 0.79 (3 H, d, J 7, 9-CH₃), 0.88 [12 H, m, SiC(CH₃)₃and

and 9.76 (1 H, d, J 3, 1-H); δ_C(CDCl₃, 125 MHz) −4.5, −4.2, 18-H₃), 1.01 and 1.03 (each 3 H, d, J 7, 2-CH₃or 7-CH₃),

10.0, 11.5, 13.9, 18.4, 19.6, 21.5, 26.0, 27.6, 30.2, 30.9, 33.7, 1.14–1.44 (8 H, m), 1.50–1.73 and 1.86–1.98 (each 2 H, m), 2.05

38.5, 42.8, 51.5, 54.5, 72.8, 75.5, 79.5, 127.2, 129.4, 137.4, 142.8 (1 H, ddd, J 13.7, 7.5 and 1.9, 5-H), 2.14 (1 H, m, 2-H), 2.42 (3

and 205.4; m/z (CI) 571 (M⁺+ 18, 2%), 554 (M⁺+ 1, 2%) and 86 H, s, ArCH₃), 2.61 (1 H, m, 5-H′), 2.65 (3 H, s, NCH₃), 3.48

(100).

(2 H, m, 10-H and 1-H), 3.54 (1 H, dd, J 9.4 and 4.4, 3-H), 3.66

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9725

Paper

(2 H, m), 3.86 (1 H, m, 4-H), 3.98 (1 H, m, 6-H), 4.1 (2 H, m), outlined for the synthesis of the Boc-protected amine 39, the

4.48 (2 H, s, PhCH₂), 7.22–7.36 (10 H, m, ArH), 7.54 (2 H, m, amine 66 (41 mg, 0.069 mmol), after chromatography using

ArH) and 7.73 (2 H, d, J 8.2, ArH); δ_C(CDCl₃, 125 MHz) −4.6 15 : 1 light petroleum : ether, gave the title compound 67

(2), 9.8, 10.8, 13.9, 14.6, 18.5, 19.6, 21.5, 26.3, 27.7, 30.1, 31.0, (45 mg, 95%) as a pale yellow oil, a 60 : 40 mixture of rotamers,

33.7, 37.0, 38.3, 39.6, 41.7, 42.4, 46.5, 54.6, 72.5, 72.8, 73.0, R_f= 0.14 (5 : 1 light petroleum : ether); [α]²_D⁷−5.1 (c 1.1 in

75.3, 78.0, 80.3, 83.6, 126.8, 127.1, 127.2, 127.5, 128.1, 129.0, CHCl₃) (Found: M⁺, 689.5043. C₄₀H₇₁NO₆Si requires M,

129.4, 130.7, 133.5, 137.4, 139.1 and 142.7; m/z (CI) 917 (M⁺+ 689.5050); ν_max/cm⁻¹1692, 1461, 1389, 1365, 1251, 1149, 1097,

18, 1%) and 106 (100).

1065, 1044, 835 and 772; δ_H(500 MHz, CDCl₃) 0.04 and 0.05

(2S,3R,6S,7R,8S,9R,10R,13S,15R)-1-B^ENZYLOXY-8-TERT-BUTYLDI- (each 3 H, s, SiCH₃), 0.78 (3 H, d, J 6.5, 7-CH₃or 9-CH₃),

^{METHYLSILYLOXY}-3,6;10,13-BIS-EPOXY-15-[N-METHYL-N-(TOLUENE-4-SULFO-

0.82–0.93 [15 H, m, SiC(CH₃)₃, 18-H₃, 9-CH₃or 7-CH₃], 0.96 (3

the H, d, J 7.0, 2-CH₃), 1.19–1.64 (12 H, m), 1.45 [9 H, s, C(CH₃)₃],

^NYL)AMINO]-2,7,9-TRIMETHYLOCTADECANE

(65). Following

procedure outlined for the deselenation of selenide 34, the 1.79–2.09 (5 H, m), 2.64 (1.2 H, s, NCH₃), 2.68 (1.8 H, s, NCH₃),

selenide 64 (750 mg, 0.834 mmol) gave the title compound 65 3.37 (1 H, t, J 7.5, 1-H), 3.48 (1 H, m), 3.55–3.68 (3 H, m), 3.83

(527 mg, 85%) as a colourless liquid, [α]¹_D⁹−9.13 (c 4.6 in (1 H, m), 3.97–4.09 (1.4 H, m, 8-H, 15-H), 4.17 (0.6 H, br. s, 15-

CHCl₃) (Found: M⁺+ NH₄, 761.4955. C₄₂H₇₃N₂O₆SSi requires H), 4.51 (2 H, s, ArCH₂) and 7.22–7.40 (5 H, m, ArH); δ_C

M, 761.4958); ν_max/cm⁻¹1599, 1495, 1462, 1384, 1343, 1251, (125 MHz; CDCl₃) −4.4, −4.2, 10.4, 10.8, 14.0, 18.7, 19.5, 19.7,

1154, 1092, 1042, 963, 921, 878, 832, 815, 774, 734, 718, 698 26.5, 28.8, 29.2, 29.5, 30.3, 30.6, 31.1, 31.4, 35.2, 35.3, 38.8,

and 657; δ_H(CDCl₃, 500 MHz) 0.05 and 0.09 (each 3 H, s, 39.1, 39.2, 41.6, 41.7, 43.3, 43.4, 52.0, 52.6, 72.7, 73.3, 73.7,

SiCH₃), 0.81 (3 H, d, J 6.7, 7-CH₃or 9-CH₃), 0.87 (3 H, t, J 7.1, 76.0, 76.4, 79.0, 79.1, 79.5, 80.5, 80.6, 127.6, 127.7, 128.5, 139

18-H₃), 0.91 [9 H, s, SiC(CH₃)₃], 0.92 (3 H, d, J 6.7, 9-CH₃or 7- and 156.4; m/z (EI) 689 (M⁺, 2%), 617 (22), 253 (74) and 213

CH₃), 0.94 (3 H, d, J 6.7, 2-CH₃), 1.15–1.68 (12 H, m), 1.82–1.98 (100).

(5 H, m), 2.41 (3 H, s, ArCH₃), 2.65 (3 H, s, NCH₃), 3.36 (1 H,

(2S,3R,6S,7R,8S,9R,10R,13S,15R)-8-^TERT-BUTYLDIMETHYLSILYLOXY-

dd, J 8.7 and 7.5, 1-H), 3.46 (1 H, dt, J 6.2, 8.7, 10-H), 3.56–3.68 3,6;10,13-^BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYLAMINO)-

(3 H, m, 1-H′, 3-H and 13-H or 15-H), 3.9 (1 H, m, 6-H), 4.09 (1 2,7,9-^{TRIMETHYLOCTADECAN}-1-OL (68). Following the procedure out-

H, m, 15-H or 13-H), 4.13 (1 H, dd, J 7.5 and 1.2, 8-H), 4.46 (2 lined for the synthesis of alcohol 40, the benzyl ether 67

H, s, PhCH₂), 7.27 (3 H, m, ArH), 7.73 (4 H, m, ArH) and 7.72 (37 mg, 0.054 mmol) was hydrogenolysed to give, after chrom-

(2 H, d, J 8.2, ArH); δ_C(CDCl₃, 125 MHz) −4.6, −4.5, 10.1, 10.5, atography using 5 : 1 light petroleum : ether, the title compound

13.9, 18.6, 19.7, 21.5, 25.2, 26.3, 27.7, 29.1, 29.3, 30.2, 31.1, 68 (26 mg, 82%), as a colourless oil, a 60 : 40 mixture of rota-

33.7, 38.3, 38.9, 41.6, 42.9, 54.7, 72.6, 72.9, 73.4, 75.2, 78.5, mers, R_f= 0.29 (2 : 1 light petroleum : ether), [α]²_D⁸+6.8 (c 1.0 in

80.4, 80.5, 127.2, 127.3, 127.5, 128.2, 129.4, 137.4, 139.1 and CHCl₃) (Found: M⁺+ H, 600.4663. C₃₃H₆₆NO₆Si requires M,

142.7; m/z (CI) 761 (M⁺+ 18, 1%), 240 (10) and 86 (100).

600.4659); ν_max/cm⁻¹3499, 1693, 1462, 1391, 1365, 1251, 1152,

(2S,3R,6S,7R,8S,9R,10R,13S,15R)-1-B^ENZYLOXY-8-TERT-BUTYLDI- 1042, 869, 836 and 723; δ_H(500 MHz, CDCl₃) 0.03 and 0.05

^{METHYLSILYLOXY}-3,6;10,13-BIS-EPOXY-15-(N-METHYLAMINO)-2,7,9-TRI- (each 3 H, s, SiCH₃), 0.76 (3 H, m, 18-H₃), 0.81 and 0.86 (each

^{METHYLOCTADECANE}(66). Following the procedure outlined for 3 H, d, J 7.1, 7-CH₃or 9-H₃), 0.87–0.95 [12 H, m, SiC(CH₃)₃, 2-

the preparation of the secondary amine 38, the sulfonamide CH₃], 1.10–2.10 (17 H, m), 1.44 [9 H, s, C(CH₃)₃], 2.62 (1.2 H, s,

65 (0.15 g, 0.20 mmol) was deprotected to give, after chromato- NCH₃), 2.67 (1.8 H, s, NCH₃), 3.45 (1 H, m), 3.49–3.64 (5 H, m),

graphy using light petroleum : ether containing 1% v/v Et₃N 3.94 (1 H, m), 3.98–4.06 (1.4 H, m, 8-H and 15-H) and

(gradient elution 3 : 1 to 1 : 1), the title compound 66 (0.10 g, 4.10–4.21 (0.6 H, m, 15-H); δ_C(125 MHz, CDCl₃) −4.4, 10.1,

83%), R_f= 0.03 (2 : 1 light petroleum : ether); [α]²_D⁶−4.0 (c 0.5 in 10.7, 10.8, 14.0(2), 14.2, 18.7, 19.4, 19.6, 26.5, 28.8, 30.4, 31.1,

CHCl₃) (Found: M⁺+ H, 590.4598. C₃₅H₆₄NO₄Si requires M, 35.2, 35.4, 38.7, 39.0, 40.1, 41.7, 41.8, 42.8, 51.9, 52.6, 69.0,

590.4604); ν_max/cm⁻¹3358, 1461, 1383, 1360, 1251, 1096, 1046, 72.6, 76.2, 76.4, 79.0, 79.4, 79.9, 80.3, 85.8 and 156.4; m/z (CI)

835, 774 and 734; δ_H(300 MHz, CDCl₃) 0.09 (6 H, s, 2 × SiCH₃), 600 (M⁺+ 1, 10%), 500 (72), and 86 (100).

0.81 and 0.89 (each 3 H, d, J 6.9, 7-CH₃or 9-CH₃), 0.90–0.95

(2R,3R,6S,7R,8S,9R,10R,13S,15R)-8-^TERT-BUTYLDIMETHYLSILYLOXY-

[12 H, m, SiC(CH₃)₃, 18-H₃), 0.98 (3 H, d, J 6.7, 2-CH₃), 3,6;10,13-^BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYLAMINO)-2,7,9-

1.12–1.69 (12 H, m), 1.80–2.07 (5 H, m), 2.41 (3 H, s, NCH₃), TRIMETHYLOCTADECANOIC ACID (70). Following the procedure out-

2.55 (1 H, br. t, J 4.5, 15-H), 3.39 (1 H, dd, J 8.9, 7.3, 1-H), lined for the oxidation of alcohol 40, the alcohol 68 (35 mg,

3.48–3.62 (2 H, m), 3.66 (1 H, dd, J 8.9, 4.4, 1-H′), 3.77–3.95 (2 0.058 mmol) was oxidised to give the aldehyde 69 (35 mg, ca.

H, m), 4.08 (1 H, d, J 7.9, 8-H), 4.52 (2 H, s, ArCH₂) and 100%) as an oil, a 50 : 50 mixture of rotamers; ν_max/cm⁻¹1729,

7.26–7.40 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) −4.4, −4.3, 10.1, 1693, 1462, 1390, 1366, 1257, 1150, 1043, 870, 836 and 773; δ_H

10.9, 14.1, 14.7, 18.8, 19.3, 26.5, 29.3, 29.4, 30.2, 32.2, 34.2, (300 MHz, CDCl₃) 0.05 and 0.06 (each 3 H, s, SiCH₃), 0.77 and

36.3, 39.0, 40.5, 41.9, 42.8, 59.5, 72.9, 73.3, 73.6, 78.5, 78.6, 0.87 (3 H, d, J 6.6, 7-CH₃or 9-CH₃), 0.89–0.96 [12 H, m, SiC-

80.5, 81.1, 127.6, 127.7, 128.5 and 139.2; m/z (CI) 590 (M⁺+ 1, (CH₃)₃and 18-H₃], 1.08 (3 H, d, J 7.0, 2-CH₃), 1.18–1.73 (20 H,

53%), 342 (22), 228 (41), 219 (50), 108 (82) and 86 (100).

m), 1.78–2.11 (5 H, m), 2.46 (1 H, m, 2-H), 2.66 and 2.70 (each

(2S,3R,6S,7R,8S,9R,10R,13S,15R)-1-B^ENZYLOXY-8-TERT-BUTYLDIMETHYLSI- 1.5 H, s, NCH₃), 3.47 and 3.62 (each 1 H, m), 3.81–4.00 (2 H,

^LYLOXY-3,6;10,13-BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYLAMINO)- m), 4.01–4.11 (1.5 H, m), 4.19 (0.5 H, m, 15-H) and 9.81 (1 H,

2,7,9-^{TRIMETHYLOCTADECANE}

(67). Following the procedure s, 1-H); m/z (CI) 598 (M⁺+ 1, 2%), 497 (16) and 86 (100).

9726 | Org. Biomol. Chem., 2012, 10, 9709–9733

This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry

Following the procedure outlined for the oxidation of the

Formalin (18 μL) and NaCNBH₃(8 mg) were added to this

aldehyde 41, the aldehyde 69 (35 mg, 0.058 mmol), after amine (10 mg, 0.024 mmol) in acetonitrile (0.3 mL), and the

chromatography 4 : 1 hexane : ether, gave the title compound 70 reaction was stirred for 1 h at room temperature. Acetic acid

(32 mg, 90%) as a colourless oil, a 50 : 50 mixture of rotamers, (5 μL) was added and the mixture stirred overnight at room

R_f= 0.36 (2 : 1 light petroleum : ether); [α]²_D⁵+2.2 (c 1.0, CHCl₃) temperature. After concentration under reduced pressure,

(Found: M⁺+ H, 614.4450. C₃₃H₆₄NO₇Si requires M, 614.4452); chromatography of the residue using 1 : 1 light petroleum :

ν_max/cm⁻¹3414, 1736, 1692, 1462, 1365, 1251, 1154, 1039, 834 ether with 1% Et₃N gave the title compound 73 (5 mg, 48%) as

and 772; δ_H(500 MHz, CDCl₃) 0.04 and 0.07 (each 3 H, s, an oil, [α]²_D²−25.7 (c 0.28 in CH₂Cl₂), lit.^5l[α]_D³⁰−33.4 (c 0.99 in

SiCH₃), 0.76 (3 H, t, J 7.0, 18-H₃), 0.82–0.96 [15 H, m, 2 × CH₃, CH₂Cl₂) (Found: M⁺, 427.3292. C₂₄H₄₅NO₅requires M,

SiC(CH₃)₃,], 1.13–1.36 (8 H, m), 1.37–1.75 (15 H, m), 1.81–2.06 427.3298); ν_max/cm⁻¹3480, 1736, 1462, 1380, 1268, 1215, 1166,

(5 H, m), 2.50 (1 H, m, 2-H), 2.63 and 2.68 (each 1.5 H, s, 1358, 963, 885, 856, 837, 757 and 666; δ_H(acetone-d₆with

NCH₃), 3.49, 3.64 and 3.84 (each 1 H, m), 3.94–4.14 (2.5 H, m) CF₃COOD, 400 MHz) 0.79 and 0.88 (each 3 H, d, J 7, 7-CH₃or

and 4.31 (0.5 H, m, 15-H); δ_C(125 MHz, CDCl₃) −4.6, −4.5, 9.5, 9-CH₃), 0.98 (3 H, t, J 7.2, 18-H₃), 1.1 (3 H, d, J 7, 2-CH₃), 1.43

9.8, 10.1, 10.3, 13.3, 13.6, 13.8, 14.0, 18.5, 18.6, 19.2, 26.2, 26.3, (2 H, m), 1.5–1.8 (8 H, m), 1.7–2.2 (6 H, m), 2.53 (1 H, m, 2-H),

27.6, 28.5, 28.7, 29.6, 29.7, 30.0, 30.1, 31.2, 31.3, 33.9, 35.3, 2.94 and 3.11 (each 3 H, s, NCH₃), 3.61 (1 H, m, 15-H), 3.63 (3

39.1, 39.2, 41.5, 41.9, 42.1, 44.6, 44.9, 51.7, 53.1, 72.6, 75.7, H, s, OCH₃), 3.75 (1 H, dd, J 9.5 and 1.8, 8-H), 3.86–3.94 (2 H,

76.3, 79.2, 79.3, 79.8, 79.9, 80.1, 80.2, 80.4, 156.0, 156.2, 176.4 m, 3-H and 10-H), 4.14 (1 H, m, 13-H) and 4.25 (1 H, m, 6-H);

and 176.6; m/z (CI) 614 (M⁺+ 1, 2%) and 86 (100).

M^ETHYL(2R,3R,6S,7R,8S,9R,10R,13S,15R)-8-TERT-BUTYLDIMETHYL-

m/z (CI) 428 (M⁺, 100%).

M^ETHYL

(S)-2-TERT-BUTYLDIPHENYLSILYLOXYPENTANOATE (75). tert-

^SILYLOXY-3,6;10,13-BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYL- Butyldiphenylsilyl chloride (19.6 g, 71.3 mmol) and imidazole

(71). Following the (14.2 g, 20.7 mmol) were added to the hydroxy ester 74 (7.8 g,

^AMINO)-2,7,9-TRIMETHYLOCTADECANOATE

procedure outlined for the synthesis of the methyl ester 43, a 59.4 mmol) in DCM (30 mL) and the mixture stirred at room

sample of the acid 70 prepared from the aldehyde 69 (28 mg, temperature for 16 h. Water (10 mL) was added and the

0.0047 mmol) was converted into the title compound 71 aqueous phase was extracted with ether (2 × 20 mL). The

(22 mg, 73%), a colourless oil, a 60 : 40 mixture of rotamers organic extracts were dried (MgSO₄) and concentrated under

(Found: M⁺+ H, 628.4606. C₃₄H₆₆NO₇Si requires M, 628.4608); reduced pressure. Chromatography of the residue using light

δ_H(CDCl₃, 300 MHz) 0.00 and 0.025 (each 3 H, s, SiCH₃), 0.74 petroleum : ether (15 : 1) gave the title compound 75 (20.3 g,

(3 H, d, J 6.7, CH₃), 0.86 [15 H, m, SiC(CH₃)₃and 2 × CH₃), 92%) as an oil, [α]²_D²−27 (c 0.9 in CHCl₃) (Found: M⁺+ NH₄,

1.08 (3 H, d, J 7.1, 2-CH₃), 1.16–1.64 (20 H, m), 1.88 (5 H, m), 388.2307. C₂₂H₃₄NO₃Si requires M, 388.2308); ν_max/cm⁻¹1753,

2.52 (1 H, m, 2-H), 2.61 (1.2 H, s, NCH₃), 2.65 (1.8 H, s, NCH₃), 1736, 1110, 1047 and 737; δ_H(CDCl₃, 300 MHz) 0.88 (3 H, t, J

3.44 and 3.58 (each 1 H, m), 3.65 (3 H, s, OCH₃), 3.82 and 3.91 7, 5-H₃), 1.13 [9 H, s, SiC(CH₃)₃], 1.30–1.52 (2 H, m, 4-H₂),

(each 1 H, m), 4.0 (1.6 H, m, 8-H and 15-H) and 4.14 (0.4 H, m, 1.65–1.82 (2 H, m, 3-H₂), 3.50 (3 H, s OCH₃), 4.27 (1 H, t, J 6,

15-H); δ_C(125 MHz, CDCl₃) −4.8, −4.5, 10.1, 10.5, 10.6, 13.2, 2-H), 7.37–7.50 (6 H, m, ArH) and 7.66–7.73 (4 H, m, ArH); δ_C

13.8, 13.9, 18.5, 19.2, 19.4, 26.2, 28.5, 28.7, 29.2, 30.0, 30.8, (CDCl₃, 75 MHz) 13.8, 17.8, 19.3, 26.8, 37.2, 51.2, 72.5, 127.4,

31.1, 35.0, 38.5, 38.9, 41.3, 41.4, 43.0, 43.2, 45.0, 51.5, 52.4, 127.5, 129.6(2) 133.2, 133.4, 135.7, 135.9 and 173.7; m/z (CI)

72.3, 75.8, 76.1, 79.2, 79.4, 79.9, 80.3, 80.4, 156.1 and 175.4; 388 (M⁺+ 18, 100%) and 293 (99).

m/z (EI) 628 (M⁺+ 1, 2%) and 514 (100).

M^ETHYL(2R,3R,6S,7R,8S,9R,10R,13S,15R)-15-DIMETHYLAMINO- procedure outlined for the synthesis of the alcohol 56, the

(S)-2-^TERT-BUTYLDIPHENYLSILYLOXYPENTAN-1-OL (76). Following the

3,6;10,13-^BIS-EPOXY-8-HYDROXY-2,7,9-TRIMETHYLOCTADECANOATE (73).⁵

ester 75 (8.7 g, 23.5 mmol) and DIBAL-H (47 mL, 1 M in

Concentrated aqueous hydrogen chloride (3 drops) was added hexanes, 47 mmol), after chromatography using light

to the carbamate 71 (30 mg, 0.048 mmol) in ethanol (1 mL) petroleum : ether (4 : 1), gave the title compound 76 (7.6 g, 94%)

and the mixture was stirred for 16 h at room temperature. Satu- as an oil, [α]²_D²+16.0 (c 0.3 in CHCl₃) (Found: M⁺+ NH₄,

rated aqueous sodium bicarbonate and ethyl acetate were 360.2357. C₂₁H₃₄NO₂Si requires M, 360.2359); ν_max/cm⁻¹3453,

added and the aqueous layer was extracted with ethyl acetate. 1472, 1463, 1111, 1044, 1005, 822, 740 and 701; δ_H(CDCl₃,

The organic extracts were dried (MgSO₄) and concentrated 300 MHz) 0.76 (3 H, t, J 7, 5-H₃), 1.10 [9 H, s, SiC(CH₃)₃],

under reduced pressure. Chromatography of the residue using 1.14–1.32 (2 H, m, 4-H₂), 1.38–1.58 (2 H, m, 3-H₂), 1.84 (1 H,

light petroleum : ether with 1% Et₃N (gradient elution 2 : 1 to br. m, OH), 3.54 (2 H, m, 1-H₂), 3.86 (1 H, m, 2-H), 7.36–7.52 (6

1 : 1) gave the secondary amine 72 (10 mg, 50%); δ_H(CDCl₃, H, m, ArH) and 7.69–7.78 (4 H, m, ArH); δ_C(CDCl₃, 75 MHz)

300 MHz) 0.69 and 0.79 (each 3 H, d, J 7, 7-CH₃or 9-CH₃), 0.84 14.0, 18.3, 19.3, 27.0, 35.7, 65.9, 73.8, 127.5, 127.7, 129.7(2),

(3 H, t, J 6.7, 18-H₃), 1.05 (3 H, d, J 7, 2-CH₃), 1.22 (3 H, m), 133.8, 134.0, 135.6 and 135.8; m/z (CI) 360 (M⁺+ 18, 70%), 282

1.48 (6 H, m), 1.64–1.98 (7 H, m), 2.29 (3 H, s, NCH₃), 2.47 (70) and 265 (100).

(2 H, m, 2-H and 15-H), 3.61 (3 H, s, OCH₃), 3.76 (1 H, m),

(S)-2-^TERT-BUTYLDIPHENYLSILYLOXY-1-IODOPENTANE (77). Imidazole

3.85 (3 H, m) and 4.04 (1 H, m); δ_C(CDCl₃, 75 MHz) 9.3, (1.0 g, 14.6 mmol), triphenylphosphine (1.9 g, 7.3 mmol) and

12.2, 13.5, 14.3, 18.8, 25.9, 28.6, 29.2, 32.0, 33.4, 35.9, iodine (1.9 g, 7.6 mmol) were added to the alcohol 76 (1.0 g,

37.5, 40.2, 40.4, 44.6, 51.6, 58.5, 71.7, 78.1, 80.4, 81.7, 82.5 2.9 mmol) in THF (5 mL) and the solution stirred at room

and 175.2.

temperature for 2 h. Saturated aqueous sodium thiosulfate was

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9727

Paper

added until the colour of the iodine had disappeared. Ether synthesis of alkenol 11, but using the enantiomeric stannane

(10 mL) was added and the aqueous phase extracted with ether (R)-3 (0.29 g, 0.6 mmol), the aldehyde 79 (0.2 g, 0.6 mmol) and

(10 mL). The organic extracts were dried (MgSO₄) and concen- tin(^IV) chloride (0.6 mL, 1.0 M in DCM, 0.6 mmol), after

trated under reduced pressure. Hexane (15 mL) was added and chromatography using 5 : 1 light petroleum : ether with 1% v/v

the suspension filtered. Concentration gave the title compound of triethylamine, gave the title compound 80 (0.28 g, 90%) as a

77 (1.3 g, 97%) as a yellow oil, [α]²_D²−23.3 (c 3.3 in CHCl₃) colourless oil containing <10% of its epimer at C(6) (¹³C

(Found: M⁺

NH₄, 470.1369. C₂₁H₃₃NOSi requires M, NMR), [α]²_D⁵+16 (c 0.1 in CHCl₃) (Found: M⁺+ H, 545.3443.

470.1378); ν_max/cm⁻¹3071, 3047, 1472, 1427, 1112, 1044, 822, C₃₅H₄₉O₃Si requires M, 545.3451); ν_max/cm⁻¹3424, 1642, 1111,

740 and 701; δ_H(CDCl₃, 300 MHz) 0.83 (3 H, t, J 7, 5-H₃), 1.12 1089 and 1049; δ_H(CDCl₃, 400 MHz) 0.65 (3 H, t, J 7, 11-H₃),

[9 H, s, SiC(CH₃)₃], 1.26 (2 H, m, 4-H₂), 1.60 (2 H, m, 3-H₂), 0.93 (3 H, d, J 7, 2-CH₃), 1.07 [9 H, s, SiC(CH₃)₃], 1.07–1.47 (4

3.18 (2 H, d, J 4, 1-H₂), 3.49 (1 H, m, 2-H), 7.39–7.52 (6 H, m, H, m, 9-H₂and 10-H₂), 1.50–1.70 (2 H, m, 7-H₂), 2.08 (1 H, m,

ArH) and 7.68–7.78 (4 H, m, ArH); δ_C(CDCl₃, 75 MHz) 13.8, 5-H), 2.19 (1 H, m, 5-H′), 2.80 (1 H, m, 2-H), 3.10 (1 H, br. s,

14.5, 17.8, 19.3, 26.9, 38.9, 71.1, 127.5(2), 129.6, 129.7, 133.7 OH), 3.21 (1 H, dd, J 8 and 9, 1-H), 3.30 (1 H, dd, J 6 and 9, 1-

and 135.8(2); m/z (CI) 470 (M⁺+ 18, 21%) and 196 (100).

H′), 3.76 (1 H, m, 6-H), 3.96 (1 H, m, 8-H), 4.50 (2 H, s,

2-[(S)-2-^TERT-BUTYLDIPHENYLSILYLOXYPENT-1-YL]-1,3-DITHIANE (78). n- PhCH₂), 5.30 (l H, dd, J 10.9, 9.7, 3-H), 5.39 (1 H, m, 4-H),

Butyllithium (18.4 mL, 1.6 M in hexanes, 29.3 mmol) was 7.26–7.46 (11 H, m, ArH) and 7.70 (4 H, m, ArH); δ_C(CDCl₃,

added to 1,3-dithiane (4.4 g, 36.7 mmol) in THF (50 mL) at 100 MHz) major isomer 13.9, 17.4, 18.0, 19.3, 27.0, 32.3, 35.9,

−20 °C. The solution was stirred at −20 °C for 1.5 h, then 39.3, 43.2, 69.2, 72.6, 72.9, 74.8, 126.1, 127.4, 127.5, 127.6(2),

allowed to warm to 0 °C and added to the iodide 77 (6.6 g, 128.3, 129.5, 129.6, 135.7 and 135.9; minor isomer 17.7, 18.4,

14.7 mmol) in THF (40 mL) at 0 °C. The mixture was stirred at 19.2, 32.5, 35.7, 38.1, 40.6, 68.0, 72.3 and 75.1; m/z (CI) 545

0 °C for 16 h before water (20 mL) and ether (40 mL) were (M⁺+ 1, 14%) and 106 (100).

added. The aqueous layer was extracted with ether (2 × 20 mL)

(2S,6S,8S,3Z)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-2-METHYL-

and the organic extracts dried (MgSO₄) and concentrated ^UNDEC-3-EN-6-YL 4-NITROBENZOATE (81). 4-Nitrobenzoic acid (2.8 g,

under reduced pressure. Chromatography of the residue using 16.7 mmol) and triphenylphosphine (5.0 g, 19.1 mmol) were

light petroleum : ether (50 : 1) gave the title compound 78 (5.7 g, added to the alcohol 80 (2.0 g, 3.9 mmol) in a mixture of ether

88%) as an oil, [α]²_D²−2.3 (c 1.7 in CHCl₃); ν_max/cm⁻¹1719, (120 mL) and toluene (40 mL) at room temperature. Diethyl

1686, 1474, 1369 and 1109; δ_H(CDCl₃, 400 MHz) 0.69 (3 H, t, J azodicarboxylate (3.0 mL, 19.1 mmol) was added dropwise and

7, 5′-H₃), 1.07 [9 H, s, SiC(CH₃)₃], 1.12–1.30 (2 H, m, 4′-H₂), the mixture was stirred for 2 h. After concentration under

1.40 (2 H, m, 3′-H₂), 1.73–1.85 (2 H, m, 1′-H and 5-H), 1.93 (1 reduced pressure, chromatography of the residue using light

H, ddd, J 14, 8, 5, 1′-H′), 2.03 (1 H, m, 5-H′), 2.55–2.74 (4 H, m, petroleum : ether (gradient elution 50 : 1 to 15 : 1) gave the title

2 × SCH₂), 4.05 (2 H, m, 1-H and 2′-H), 7.36–7.46 (6 H, m, ArH) compound 81 (1.9 g, 70%) as a colourless oil, [α]²_D⁵+3.2 (c 1.5 in

and 7.69–7.74 (4 H, m, ArH); δ_C(CDCl₃, 100 MHz) 14.0, 17.9, CHCl₃) (Found: M⁺+ NH₄, 711.3819. C₄₆H₅₂N₂O₆Si requires M,

19.6, 26.0, 27.2, 30.0, 30.5, 39.3, 42.4, 44.2, 69.9, 127.4, 129.4, 711.3829); ν_max/cm⁻¹1723, 1661, 1528, 1349, 1273 and 1108;

134.3 and 135.9; m/z (CI) 387 (M⁺− 57, 15%) and 367 (100).

δ_H(CDCl₃, 300 MHz) 0.68 (3 H, t, J 7, 11-H₃), 0.93 (3 H, d, J 7,

(S)-3-^TERT-BUTYLDIPHENYLSILYLOXYHEXANAL (79). Red mercury(II) 2-CH₃), 1.01 [9 H, s, SiC(CH₃)₃], 1.29 (2 H, m, 10-H₂), 1.44 (2 H,

oxide (3.0 g, 11.7 mmol) was added to the dithiane 78 (2.7 g, m, 9-H₂), 1.82 (1 H, ddd, J 4, 8 and 14, 7-H), 1.91 (1 H, m, 7-

60.1 mmol) in THF (36 mL) containing water (4 mL). Boron tri- H′), 2.35 (1 H, m, 5-H), 2.47 (1 H, m, 5-H′), 2.75 (1 H, m, 2-H),

fluoride diethyl etherate (3.7 mL, 30.6 mmol) was added and 3.25 (2 H, d, J 7, 1-H₂), 3.79 (1 H, m, 8-H), 4.43 and 4.48 (each

the mixture stirred for 45 min. After partial concentration 1 H, d, J 12, PhHCH), 5.24 (1 H, m, 6-H), 5.35 (2 H, m, 3-H and

under reduced pressure, ether (100 mL) was added and the 4-H), 7.14–7.43 (11 H, m, ArH), 7.61 (4 H, m, ArH) and 8.03

mixture filtered. The filtrate was washed with saturated and 8.23 (each 2 H, d, J 8, ArH); m/z (CI) 712 (30%) and 106

aqueous sodium hydrogen carbonate (3 × 30 mL) and then (100). (2S,8S,3Z,5EZ)-1-Benzyloxy-8-tert-butyldiphenylsilyloxy-2-

dried (MgSO₄). After concentration under reduced pressure, methylundeca-3,5-diene (0.25 g, 12%) was also isolated as a

chromatography of the residue using light petroleum : ether 6 : 4 mixture of E : Z-isomers, a colourless oil, [α]²_D⁵−20 (c 0.6 in

(15 : 1) gave the title compound 79 (1.9 g, 98%) as a colourless CHCl₃) (Found: M⁺+ NH₄, 544.3615. C₃₅H₅₀O₂NSi requires M,

oil [α]²_D²+4.0 (c 0.9 in CHCl₃) (Found: M⁺+ NH₄, 372.2358. 544.3611); ν_max/cm⁻¹1471, 1454, 1389, 1040, 1110, 822 and

C₂₂H₃₄NO₂Si requires M, 372.2359); ν_max/cm⁻¹1725, 1463, 738; δ_H(CDCl₃, 500 MHz) 0.68 (3 H, t, J 7, 11-H₃), 0.92 [12 H,

1427, 1365, 1109 and 1039; δ_H(CDCl₃, 300 MHz) 0.76 (3 H, t, J m, 2-CH₃and SiC(CH₃)₃], 1.20 (2 H, m, 10-H₂), 1.34 (2 H, m, 9-

7, 6-H₃), 1.09 [9 H, s, SiC(CH₃)₃], 1.28 (2 H, m, 5-H₂), 1.51 (2 H, H₂), 2.14 (1 H, m, 7-H), 2.22 (1 H, m, 7-H′), 2.84 (1 H, m, 2-H),

m, 4-H₂), 2.50 (2 H, m, 2-H₂), 4.24 (1 H, quin, J 5.8, 3-H), 3.24 (2 H, m, 1-H₂), 3.69 (1 H, m, 8-H), 4.40 and 4.45 (each 1

7.37–7.52 (6 H, m, ArH), 7.60–7.8 (4 H, m, ArH) and 9.75 (1 H, H, d, J 12, PhHCH), 5.05 (0.6 H, t, J 10, 3-H), 5.12 (0.4 H, t, J 10,

t, J 3, 1-H); δ_C(CDCl₃, 75 MHz) 13.8, 18.1, 19.2, 26.9, 39.5, 3-H), 5.34 (0.4 H, m, 6-H), 5.50 (0.6 H, dt, J 7 and 15, 6-H), 5.83

50.1, 69.0, 127.5, 127.6, 129.6, 129.7, 133.6, 133.8, 135.8(2) and (0.6 H, t, J 11, 4-H), 5.91 (0.4 H, t, J 11, 4-H), 6.10 (0.6 H, dd, J

202.2; m/z (CI) 372 (M⁺+ 18, 100%) and 355 (41).

11 and 13, 5-H), 6.18 (0.4 H, t, J 11, 5-H), 7.17–7.36 (11 H, m,

(2S,6R,8S,3Z)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-2-METHYL- ArH) and 7.60 (4 H, m, ArH); δ_C(CDCl₃75 MHz) 14.1, 17.7,

^UNDEC-3-EN-6-OL (80). Following the procedure outlined for the 17.9, 18.1, 19.3, 27.0, 32.4, 32.7, 34.6, 38.4, 38.5, 40.0, 72.7,

9728 | Org. Biomol. Chem., 2012, 10, 9709–9733

Organic & Biomolecular Chemistry

72.8, 75.1, 123.9, 125.0, 127.4(2), 127.7, 128.2, 128.3, 128.9, compound 84 (70 mg, 99%) as a colourless oil containing ca.

129.4, 131.2, 132.3, 134.3, 134.5, 135.8 and 135.9; m/z (CI) 544 20% of a side-product that was not separated, [α]²_D⁵+14 (c 0.4

(M⁺+ 18, 80%) and 271 (100).

in CHCl₃); (Found: M⁺, 544.3386. C₃₅H₄₈O₃Si requires M,

(2S,6S,8S,3Z)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-2-METHYL- 544.3373); ν_max/cm⁻¹1730, 1284, 1122, 1073 and 833; δ_H

^UNDEC-3-EN-6-OL (82). Solid sodium hydroxide (0.9 g, (CDCl₃, 400 MHz) 0.68 (3 H, t, J 7, 11-H₃), 0.95 (3 H, d, J 7, 2-

22.5 mmol) was added to a suspension of the ester 81 (2.0 g, CH₃), 1.05 [9 H, s, SiC(CH₃)₃], 1.16–1.82 (11 H, m, 2-H, 4-H₂, 5-

2.9 mmol) in methanol (10 mL) and the mixture was stirred at H₂, 7-H₂, 9-H₂and 10-H₂), 3.30 (1 H, dd, J 7 and 9, 1-H), 3.43

room temperature for 2 h then concentrated under reduced (1 H, dd, J 6 and 9, 1-H′), 3.65, 3.82 and 3.93 (each 1 H, m, 3-

pressure. Ether (20 mL) and saturated aqueous ammonium H, 6-H or 8-H), 4.43 and 4.51 (each 1 H, d, J 12, PhHCH),

chloride (50 mL) were added and the aqueous phase was 7.30–7.42 (11 H, m, ArH) and 7.67–7.73 (4 H, m, ArH); δ_C

extracted with ether (3 × 20 mL). The organic extracts were (CDCl₃, 75 MHz) 13.1, 14.0, 17.6, 19.4, 27.1, 28.7, 31.5, 38.5,

dried (MgSO₄) and concentrated under reduced pressure. 39.4, 43.0, 71.1, 73.0, 73.6, 75.6, 80.2, 127.3, 128.2, 129.3,

Chromatography of the residue using 5 : 1 light petroleum : 134.5, 134.9, 135.9(2) and 138.7; m/z (CI) 545 (M⁺+ 1, 2%) and

ether gave the title compound 82 (1.4 g, 94%) as a colourless 91 (100).

oil, [α]²_D⁵+24 (c 0.2 in CHCl₃) (Found: M⁺+ H, 545.3453.

(2R,3R,6S,8S)-8-^TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-2-METHYLUN-

C₃₅H₄₉O₃Si requires M, 545.3451); ν_max/cm⁻¹3516, 1723, 1606, ^DECAN-1-OL (85). Palladium (0.02 g, 10% wt on activated carbon)

1529, 1349, 1273, 1107, 873 and 703; δ_H(CDCl₃, 400 MHz) 0.65 was added to the benzyl ether (84) (0.21 g, 0.39 mmol) in

(3 H, t, J 7, 11-H₃), 0.98 (3 H, d, J 7, 2-CH₃), 1.07 [9 H, s, SiC- ethanol (10 mL) at room temperature. The suspension was

(CH₃)₃], 1.35–1.71 (6 H, m, 7-H₂, 9-H₂and 10-H₂), 2.15–2.30 (2 stirred under one atmosphere of hydrogen overnight then fil-

H, m, 5-H₂), 2.81 (1 H, m, 2-H), 3.29 (1 H, br. s, OH), 3.30 (2 H, tered through Celite® and the filtrate was concentrated under

m, 1-H₂), 3.92–4.01 (2 H, m, 6-H and 8-H), 4.49 and 4.52 (each reduced pressure. Chromatography of the residue using 8 : 1

1 H, d, J 14, PhHCH), 5.34 (1 H, dd, J 10.8, 9.6, 3-H), 5.37 (1 H, light petroleum : ether gave the title compound 85 (0.16 g, 89%)

dt, J 11.2, 7.0, 4-H), 7.24–7.47 (11 H, m, ArH) and 7.68–7.74 (4 as a colourless oil, [α]²_D⁵+12 (c 0.4 in CHCl₃) (Found: M⁺+ H,

H, m, ArH); δ_C(CDCl₃, 100 MHz) 14.0, 17.8, 18.5, 19.4, 27.1, 455.2974. C₂₈H₄₃O₃Si requires M, 455.2981); δ_H(CDCl₃,

32.6, 35.8, 38.2, 40.7, 68.1, 72.3, 72.9, 75.2, 125.6, 127.4, 127.5, 400 MHz) 0.69 (3 H, t, J 8, 11-H₃), 0.84 (3 H, d, J 7, 2-CH₃), 1.06

127.6, 128.2, 129.6, 129.7, 133.5, 133.9, 135.2, 135.9 and 138.5; [9 H, s, SiC(CH₃)₃], 1.18–1.40 (4 H, m, 9-H₂and 10-H₂),

m/z (CI) 545 (M⁺+ 1, 32%) and 106 (100).

(2R,3S,4S,6R,8S)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY- 3.53 (1 H, dd, J 4 and 12, 1-H), 3.62 (1 H, dd, J 7 and 12, 1-H′),

(83). N-Phenylselenophthali- 3.83 (2 H, m, 3-H and 6-H), 3.92 (1 H, dq, J 7.0 and 5.5, 8-H),

1.54–1.88 (6 H, m, 4-H₂, 5-H₂and 7-H₂), 1.96 (1 H, m, 2-H),

2-^METHYL-4-PHENYLSELENOUNDECANE

mide (0.25 g, 0.84 mmol) was added to the alcohol 82 (0.3 g, 7.35–7.45 (6 H, m, ArH) and 7.68–7.72 (4 H, m, ArH); δ_C

0.56 mmol) in DCM (6 mL) at room temperature followed by (CDCl₃, 100 MHz) 12.0, 14.1, 17.8, 19.6, 26.7, 27.2, 31.5, 37.8,

tin(^IV) chloride (0.11 mL, 1.0 M in DCM, 0.11 mmol). The 39.7, 42.8, 66.3, 71.0, 76.2, 82.4, 127.3(2), 129.3, 129.4, 134.3,

mixture was stirred for 40 min before saturated aqueous 134.7, 135.8, 135.9; m/z (CI) 455 (M⁺+ 1, 3%), 377 (65) and 299

sodium bicarbonate (10 mL) was added. The aqueous phase (100).

was extracted with DCM (3 × 10 mL) and the organic extracts

B^ENZYL

(2S,3R,6S,8S)-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-2-

were dried (MgSO₄) and concentrated under reduced pressure. METHYLUNDECANOATE (88). The Dess–Martin periodinane (1.2 g,

Chromatography of the residue using light petroleum : ether 2.9 mmol) was added to the alcohol 85 (0.44 g, 0.96 mmol) in

(gradient elution 50 : 1 to 25 : 1) gave the title compound 83 DCM (15 mL) and the suspension stirred at room temperature

(0.32 g, 81%) as a yellow oil containing ca. 20% of a side- for 1 h. Saturated aqueous sodium bicarbonate (15 mL) and

product that was not separated, [α]²_D⁵+19 (c 0.4 in CHCl₃) saturated aqueous sodium thiosulfate (15 mL) were added and

(Found: M⁺+ NH₄, 718.3181. C_4lH₅₆NO₃Si⁸⁰Se requires M, the mixture was stirred at room temperature for an extra

718.3194); ν_max/cm⁻¹1732, 1455, 1427, 1362, 1286, 1110, 1073, 30 min. The aqueous phase was extracted with ether (2 ×

737 and 701; δ_H(CDCl₃, 300 MHz) 0.68 (3 H, t, J 7, 11-H₃), 1.06 15 mL) and the organic extracts were dried (MgSO₄) and con-

[9 H, s, SiC(CH₃)₃], 1.09 (3 H, d, J 7, 2-CH₃), 1.18–2.48 (9 H, m, centrated under reduced pressure to yield the aldehyde 86; δ_H

2-H, 5-H₂, 7-H₂, 9-H₂and 10-H₂), 3.38 (1 H, dd, J 6 and 9, 1-H), (CDCl₃, 300 MHz) 0.62 (3 H, t, J 7.2, 11-H₃), 0.96 [12 H, m, 2-

3.45 (1 H, dd, J 5 and 9, 1-H′), 3.51–4.06 (4 H, m, 3-H, 4-H, 6-H CH₃and SiC(CH₃)₃], 1.06–1.62 (8 H, m), 1.70–1.98 (2 H, m),

and 8-H), 4.42 and 4.48 (each 1 H, d, J 12, PhHCH), 7.22–7.48 2.39 (1 H, m, 2-H), 3.72–3.92 (3 H, m, 3-H, 6-H and 8-H),

(16 H, m, ArH) and 7.68–7.40 (4 H, m, ArH); m/z (CI) 718 (M⁺+ 7.20–7.40 (6 H, m, ArH), 7.55–7.65 (4 H, m, ArH) and 9.60

18, 2.5%) and 106 (l00).

(1 H, d, J 1.2, 1-H).

(2R,3R,6S,8S)-1-B^ENZYLOXY-8-TERT-BUTYLDIPHENYLSILYLOXY-3,6-EPOXY-

This aldehyde 86 was taken up in tert-butanol : water

2-^{METHYLUNDECANE}(84). Tributyltin hydride (76 mg, 0.26 mmol) (50 : 50, 30 mL). 2-Methyl-2-butene (7 mL), sodium chlorite

and α-azobis-isobutyronitrile (cat.) were added to the phenylse- (0.54 g, tech. 80%, 4.8 mmol) and sodium dihydrogen phos-

lenide 83 (90 mg, 0.013 mmol) in benzene (5 mL). The reaction phate (1.2 g, 9.7 mmol) were added and the reaction mixture

mixture was degassed for 20 min, heated under reflux for 2.5 h was stirred at room temperature for 2 h. Brine (30 mL and

then concentrated under reduced pressure. Chromatography ethyl acetate (50 mL) were added and the aqueous phase was

of the residue using 20 : 1 light petroleum : ether gave the title extracted with ethyl acetate (3 × 30 mL). The organic extracts

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9729

Paper

were dried (MgSO₄) and concentrated under reduced pressure (c 2.0 in benzene); (Found: M⁺+ H, 217.1807. C₁₂H₂₅O₃

to give the carboxylic acid 87; δ_H(CDCl₃, 300 MHz) 0.64 (3 H, t, requires M, 217.1803); ν_max/cm⁻¹3338, 1662, 1464, 1374 and

J 7.2, 11-H₃), 0.97 [9 H, s, SiC(CH₃)₃], 1.06 (3 H, d, J 7.1, 1038; δ_H(CDCl₃, 400 MHz) 0.91 (6 H, m, 11-H₃and 2-CH₃),

2-CH₃), 0.70–1.64 (10 H, m), 2.59 (1 H, dq, J 5.4, 7.2, 2-H), 3.72 1.30–1.78 (8 H, m, 4-H₂, 5-H₂, 9-H₂and 10-H₂), 1.84–2.04 (3 H,

(1 H, m), 3.85 (2 H, m), 7.20–7.40 (6 H, m, ArH) and 7.55–7.65 m, 2-H and 7-H₂), 2.52 (2 H, br. s, 2 × OH), 3.56 (1 H, dd, J 4

(4 H, m, ArH).

and 11, 1-H), 3.66 (1 H, dd, J 7 and 11, 1-H′), 3.83 (1 H, m, 6-H

This acid 87 was dissolved in acetonitrile (12 mL) and or 8-H), 3.97 (1 H, dt, J 4.4, 7.6, 3-H), 4.09 (1 H, dq, J 4.0, 7.6,

benzyl bromide (0.23 mL, 1.9 mmol) and N,N-di-isopropylethyl- 6-H or 8-H); δ_C(CDCl₃, 100 MHz) 12.2, 14.2, 19.0, 27.4,

amine (0.4 mL, 2.4 mmol) were added. The resulting solution 31.2, 38.6, 39.8, 41.6, 66.0, 68.9, 76.8 and 82.3; m/z (CI) 234

was stirred at room temperature for 16 h. Water (15 mL) and (M⁺+ 18, 20%) and 217 (M⁺+ 1, 100).

ether (15 mL) were added and the aqueous phase was extracted

(2R,3R,6S,8S)-1,8-^BIS-(4-BROMOBENZOYLOXY)-3,6-EPOXY-2-METHYLUN-

with ether (2 × 15 mL). The organic extracts were dried ^DECANE(91).⁵4-Bromobenzoyl chloride (0.36 mL, 2.8 mmol),

(MgSO₄) and concentrated under reduced pressure. Chromato- triethylamine (0.46 mL, 3.3 mmol) and DMAP (cat.) were

graphy of the residue using 50 : 1 light petroleum : ether gave added to the diol 90 (12 mg, 0.055 mmol) in DCM (0.5 mL)

the title compound 88 (0.41 g, 76% overall) as a colourless oil, and the mixture stirred for 16 h. Water (1 mL) was added and

[α]²_D⁵12.7 (c 4.2 in CHCl₃) (Found: M⁺+ NH₄, 576.3504. the aqueous phase extracted with DCM (3 × 2 mL). The organic

C₃₅H₅₀NO₄Si requires M, 576.3509); ν_max/cm⁻¹1734, 1461, extracts were dried (MgSO₄) and concentrated under reduced

1273, 1108 and 1067; δ_H(CDCl₃, 400 MHz) 0.60 (3 H, t, J 7, 11- pressure. Chromatography of the residue using 5 : 1 light

H₃), 0.97 [9 H, s, SiC(CH₃)₃], 1.16 (3 H, d, J 7, 2-CH₃), 1.18 (2 H, petroleum : ether gave the title compound 91 (14 mg, 43%) as

m, 10-H₂), 1.27 (2 H, m, 9-H₂), 1.42–1.80 (6 H, m, 4-H₂, 5-H₂a colourless oil, [α]²_D⁵+27 (c 4 in CHCl₃), lit.^5j+25 (c 0.28 in

and 7-H₂), 2.39 (1 H, m, 2-H), 3.73–3.88 (3 H, m, 3-H, 6-H and CHCl₃) (Found: M⁺+ H, 581.0544. C₂₆H₃₁O₅⁷⁹Br₂requires M,

8-H), 5.00 and 5.04 (each 1 H, d, J 12, PhHCH), 7.22–7.38 (11 581.0539); ν_max/cm⁻¹1719, 1590, 1270, 1103, 1011 and 755; δ_H

H, m, ArH) and 7.60–7.68 (4 H, m, ArH); δ_C(CDCl₃, 75 MHz) (CDCl₃, 400 MHz) 0.93 (3 H, t, J 7, 11-H₃), 1.05 (3 H, d, J 7, 2-

14.0, 14.2, 17.7, 19.5, 27.1, 29.3, 31.3, 39.5, 43.1, 45.5, 66.1, CH₃), 1.33–1.76 (6 H, m, 4-H, 5-H, 9-H₂and 10-H₂), 1.86–2.00

71.1, 76.2, 79.7, 127.4, 128.1(2), 128.5, 128.8, 129.4, 130.9, (4 H, m, 4-H′, 5-H′ and 7-H₂), 2.04 (1 H, m, 2-H), 3.80 (1 H, q, J

134.4, 134.9, 135.9, 136.0 and 174.5; m/z (CI) 576 (M⁺+ 18, 2%) 5.5, 3-H), 3.91 (1 H, quin, J 6.5, 6-H), 4.19 (1 H, dd, J 7, 11, 1-

and 91 (l00).

H), 4.29 (1 H, dd, J 6 and 11, 1-H′), 5.28 (1 H, quin, J 6.2, 8-H)

B^ENZYL(2S,3R,6S,8S)-3,6-EPOXY-8-HYDROXY-2-METHYLUNDECANOATE and 7.56–7.62 and 7.87–7.92 (each 4 H, m, ArH); δ_C(CDCl₃,

(89). The silyl ether 88 (26 mg, 0.047 mmol) was dissolved in 100 MHz) 13.1, 14.1, 18.5, 28.7, 31.8, 37.0, 37.6, 40.5, 67.7,

trifluoromethanesulfonic acid and water (1.0 mL, 9 : 1) and the 73.3, 76.0, 80.1, 127.7, 127.9, 129.2, 129.5, 131.0, 131.6, 165.3

solution was stirred at room temperature for 40 min. Ether and 165.7; m/z (CI) 585, 583, 581 (M⁺+ 1, 25, 50, 25%) and 183

(3 mL) and saturated aqueous sodium hydrogen carbonate (100).

(5 mL) were added cautiously and the aqueous phase was

B^ENZYL(2S,3R,6S,8S)-8-{(2R,3R,6S,7R,8S,9R,10R,13S,15R)-8-TERT-

extracted with ether (3 × 5 mL). The organic extracts were dried BUTYLDIMETHYLSILYLOXY-3,6;10,13-BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBO-

(MgSO₄) and concentrated under reduced pressure. Chromato- ^NYL-N-METHYLAMINO)-2,7,9-TRIMETHYLOCTADECANOYLOXY}-3,6-EPOXY-2-

graphy of the residue using 6 : 1 light petroleum : ether gave METHYLUNDECANOATE (92). DMAP (43 mg, 0.355 mmol) and 2,4,6-

the title compound 89 (14 mg, 94%) as a colourless oil, [α]²_D⁵trichlorobenzoyl chloride (19 μL, 0.122 mmol) were added to

+16.6 (c 0.7 in CHCl₃) (Found: M⁺+ H, 321.2067. C₁₉H₂₉O₄the undecanol 89 (30 mg, 0.094 mmol) and the octadecanoic

requires M, 321.2066); ν_max/cm⁻¹3445, 1732, 1459, 1376, 1158, acid 70 (57 mg, 0.094 mmol) in DCM (0.92 mL) and the

1056 and 746; δ_H(CDCl₃, 400 MHz) 0.94 (3 H, t, J 7, 11-H₃), mixture stirred at room temperature for 3.5 h. Aqueous citric

1.26 (3 H, d, J 7, 2-CH₃), 1.30–1.96 (10 H, m, 4-H₂, 5-H₂, 7-H₂, acid (10%, 1.5 mL) was added and the aqueous layer was

9-H₂and 10-H₂), 2.62 (1 H, quin, J 7.1, 2-H), 3.84 (1 H, m, 8-H), extracted with DCM (3 × 5 mL). The organic extracts were

4.01 (1 H, q, J 7.1, 3-H), 4.11 (1 H, m, 6-H), 5.12 and 5.15 (each washed with saturated aqueous sodium bicarbonate (10 mL),

1 H, d, J 12, PhHCH), and 7.31–7.40 (5 H, m, ArH); δ_C(CDCl₃, water (10 mL) and brine (10 mL) then dried (MgSO₄) and con-

100 MHz) 14.1, 14.2, 19.1, 29.1, 30.9, 39.6, 41.2, 45.1, 66.3, centrated under reduced pressure. Chromatography of the

68.9, 77.2, 80.5, 128.1(2), 128.5, 135.9 and 174.1; m/z (CI) 338 residue using 5 : 1 light petroleum : ether gave the title com-

(M⁺+ 18, 33%), 321 (M⁺+ 1, 100) and 320 (4).

pound 92 (67 mg, 78%), as an oil, a 40 : 60 mixture of rotamers,

(2R,3R,6S,8S)-3,6-E^POXY-2-METHYLUNDECAN-1,8-DIOL (90).¹Con- R_f= 0.60 (1 : 1 light petroleum : ether), [α]²_D⁵+1.5 (c 1.1 in

centrated aqueous hydrogen chloride (50 μL) was added drop- CHCl₃) (Found: M⁺+ NH₄, 933.6593. C₅₂H₉₃N₂O₁₀Si requires

wise to the silyl ether 85 (25 mg, 0.055 mmol) in methanol M, 933.6594); ν_max/cm⁻¹1734, 1692, 1460, 1389, 1365, 1338,

(0.7 mL) and the mixture heated under reflux for 2.5 h. After 1253, 1156, 1049, 836, 773 and 698; δ_H(500 MHz, CDCl₃,) 0.03

cooling to room temperature, saturated aqueous sodium bicar- and 0.05 (each 1.5 H, s, SiCH₃), 0.08 (3H, s, SiCH₃), 0.78 (3 H,

bonate (1 mL) was added and the mixture concentrated under br. d, J 6.5, CH₃), 0.85–0.96 [18 H, m, SiC(CH₃)₃and 3 × CH₃),

reduced pressure. Chromatography of the residue using 1 : 1 1.09 (3 H, d, J 7.0, CH₃), 1.25 (3 H, d, J 7, CH₃), 1.48 [9 H, s,

light petroleum : ether gave the title compound 90 (12 mg, C(CH₃)₃], 1.18–2.05 (26 H, m), 2.48–2.57 (2 H, m, 2-H and 2′-H),

99%) as a colourless oil, [α]²_D⁵+4.4 (c 1.2 in CHCl₃), lit.^1c+7.2 2.63 (1.2 H, s, NCH₃), 2.67 (1.8 H, s, NCH₃), 3.45, 3.59, 3.73

9730 | Org. Biomol. Chem., 2012, 10, 9709–9733

Organic & Biomolecular Chemistry

and 3.85 (each 1 H, m), 3.91–4.00 (2 H, m), 4.01–4.08 (1.4 H, under reduced pressure gave the title compound 94 (38 mg,

m, 8′-H and 15′-H), 4.18 (0.6 H, m, 15′-H), 4.99 (1 H, m, 8-H), 97%), as an oil, a 40 : 60 mixture of rotamers, R_f= 0.11 (1 : 2

5.12 (2 H, s, PhCH₂) and 7.30–7.39 (5 H, m, ArH); δ_C(125 MHz, light petroleum : ether) (Found: M⁺

Na, 734.4814.

CDCl₃) −4.8, −4.4, 10.4, 11.1(2), 12.9, 13.0, 13.8, 13.9, 14.0, C₃₉H₆₉NO₁₀Na requires M, 734.4819); ν_max/cm⁻¹3474, 1732,

14.1, 18.3, 18.4, 19.2, 19.4, 26.1, 28.2, 28.3, 28.4, 28.5, 29.2, 1691, 1460, 1365, 1255, 1153, 1058, 956, 875 and 770; δ_H

29.5, 29.9, 30.3(2), 30.7, 31.0, 31.5, 35.0, 36.9, 38.4, 38.8, 40.6, (300 MHz, CDCl₃,) 0.79 (3 H, d, J 6.9, CH₃), 0.84–1.00 (9 H, m,

41.2, 41.3, 43.8, 43.9, 45.1, 45.2, 45.4, 51.6, 52.3, 66.1, 72.0, 3 × CH₃), 1.12 (3 H, d, J 7.2, CH₃), 1.20 (3 H, d, J 6.9, CH₃),

72.1, 75.8, 76.1, 76.7, 79.2, 79.5, 79.9, 80.0, 80.1, 80.5, 80.6, 1.22–2.15 (28 H, m), 1.45 [9 H, s, C(CH₃)₃], 2.54 (1 H, m, 2-H or

128.1(2), 128.5, 136.0, 174.4 and 174.6; m/z (APCI⁺) 916 (M⁺+ 2′-H), 2.64 (1.2 H, s, NCH₃), 2.68 (1.8 H, s, NCH₃), 2.74 (1 H,

1, 6%) and 120 (100).

B^ENZYL

m, 2-H or 2′-H), 3.63–4.28 (8 H, m) and 5.03 (1 H, m, 8-H); m/z

(2S,3R,6S,8S)-8-{(2R,3R,6S,7S,8S,9S,10R,13S,15R)- (APCI⁺) 734 (M⁺+ 23, 100%), 612 (16%), 528 (17), 427 (49), 330

3,6;10,13-^BIS-EPOXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYLAMINO)-

(48), 267 (40), 211 (47) and 196 (86).

8-^HYDROXY-2,7,9-TRIMETHYLOCTADECANOYLOXY}-3,6-EPOXY-2-METHYLUNDE-

N-^TERT-BUTOXYCARBONYL-N-DESMETHYLPAMAMYCIN 607 (95). Tri-

^CANOATE(93). Concentrated aqueous hydrogen chloride (3 ethylamine (8 mg, 0.079 mmol) and 2,4,6-trichlorobenzoyl

drops) was added to the silyl ether 92 (56 mg, 0.061 mmol) in chloride (12.0 μL, 0.079 mmol) were added to the seco-acid 94

ethanol (3 mL) and the mixture heated at 55 °C for 3.5 h. After (40 mg, 0.056 mmol) in xylene (3.9 mL) and the mixture

cooling to room temperature, the mixture was concentrated stirred at room temperature for 14 h. DMAP (20 mg) in xylene

under reduced pressure and the residue dissolved in ethyl (6 mL) was added and the mixture stirred at room temperature

acetate (3 mL). Saturated aqueous sodium bicarbonate (3 mL) for 24 h. Saturated aqueous ammonium chloride was added

was added and the aqueous fraction extracted with ethyl and the mixture extracted into ethyl acetate. The organic

acetate (3 × 10 mL). The organic extracts were dried (MgSO₄) extracts were dried (MgSO₄) and concentrated under reduced

and concentrated under reduced pressure. The residue was pressure. Chromatography of the residue using light

dissolved in DCM (1.6 mL) and di-tert-butyl dicarbonate petroleum : ether (2 : 1) gave the title compound 95 (10 mg,

(0.027 g, 0.122 mmol) was added followed by Et₃N 25%), as an oil, a 40 : 60 mixture of rotamers, R_f= 0.50 (1 : 2

(0.184 mmol, 0.18 μL). The mixture was stirred for 16 h at light petroleum : ether) (Found: M⁺+ H, 694.4900. C₃₉H₆₈NO₉

room temperature then water (2 mL) was added. The aqueous requires M, 694.4889); δ_H(400 MHz, CDCl₃,) 0.81 (3 H, t, J 7.5,

layer was extracted with DCM (3 × 5 mL) and the organic 18-H₃or 11-H₃), 0.85–0.96 (12 H, m, 4 × CH₃), 1.08 (3 H, d, J

extracts were washed with water (10 mL) and brine (10 mL). 7.0, CH₃), 1.45 [9 H, s, C(CH₃)₃], 1.18–2.08 (26 H, m), 2.35 (1 H,

After drying (MgSO₄) and concentration under reduced m, 2-H or 2′-H), 2.59 (1 H, qd, J 7.1, 3.0, 2′-H or 2-H), 2.64 (1.2

pressure, chromatography of the residue using light H, s, NCH₃), 2.67 (1.8 H, s, NCH₃), 3.59–3.73 (1 H, m),

petroleum : ether (gradient elution 2 : 1 to 1 : 1) gave the title 3.74–3.88 and 3.90–4.20 (each 3 H, m) and 4.85–4.99 (2 H, m,

compound 93 (46 mg, 93%), as an oil, a 40 : 60 mixture of rota- 8-H and 8′-H); m/z (APCI⁻) 692 (M⁺− 1, 28%), 434 (21), 212

mers, R_f= 0.11 (1 : 1 light petroleum : ether), [α]²_D⁷−8.2 (c 1.1 in (60) and 174 (100); (ES⁺) 716 (M⁺+ 23, 100). A less polar com-

CHCl₃) (Found: M⁺+ NH₄, 819.5727. C₄₆H₇₉N₂O₁₀requires M, pound (12 mg) was also isolated and identified as a dimer, m/z

819.5729); ν_max/cm⁻¹3499, 1732, 1691, 1457, 1365, 1254, 1154, (ES⁺) 1410 (M⁺+ 23, 100%), but was not fully charactered.

1057 and 751; δ_H(500 MHz, CDCl₃) 0.78 (3 H, d, J 7.0, CH₃),

P^AMAMYCIN607 (1).¹Trifluoroacetic acid in DCM (6.5 M,

0.85–0.95 (9 H, m, 3 × CH₃), 1.10 and 1.25 (each 3 H, d, J 7.0, 0.1 mL, 0.65 mmol) was added to the carbamate 95 (10 mg,

CH₃), 1.25–1.80 (18 H, m), 1.45 [9 H, s, C(CH₃)₃], 1.81–2.04 (9 0.014 mmol) at room temperature and the solution stirred for

H, m), 2.49–2.58 (2 H, m, 2-H and 2′-H), 2.63 (1.2 H, br. s, 45 min. DCM (5 mL) and saturated aqueous sodium hydrogen

NCH₃), 2.66 (1.8 H, s, NCH₃), 3.71 (1 H, m), 3.75–3.86 (2 H, m), carbonate (5 mL) were added and the aqueous phase, now

3.88 (1 H, br. d, J 8.5), 3.94 (2 H, m), 4.02–4.12 (1.4 H m, 8′-H with pH ca. 7, was extracted with DCM (5 × 5 mL). The organic

and 15′-H), 4.22 (0.6 H m, 15′-H), 4.99 (1 H, m, 8-H), 5.12 (2 H, extracts were dried (MgSO₄) and concentrated under reduced

s, ArCH₂) and 7.30–7.39 (5 H, m, ArH); δ_C(125 MHz, CDCl₃) pressure to leave desmethyl pamamycin 607 (96);^1dδ_H

9.2, 12.1, 13.2, 13.7, 14.0, 14.1, 18.3, 19.1, 26.6(2), 28.5(2), 29.0, (400 MHz, CDCl₃,) 0.78 (3 H, d, J 7.0, CH₃), 0.85 (3 H, d, J 6.5,

29.2, 30.3, 31.1, 31.5, 35.1, 36.8, 37.8, 38.7, 40.5, 45.0, 45.4, CH₃), 0.89 (3 H, t, J 7.3, 18-H₃or 11′-H₃), 0.96 (3 H, t, J 7.4, 18-

51.6, 66.1, 71.8, 72.3, 76.6, 79.2, 79.9, 80.2, 81.6, 82.1, 128.1(2), H₃or 11′-H₃), 1.07 (6 H, d J 7.0, 2 × CH₃), 1.20–2.07 (26 H, m),

128.5, 136.0, 174.44, 174.52; m/z (CI) 819 (M⁺+ 18, 100%) and 2.28 (1 H, dq, J 9.8, 7.0, 2-H or 2′-H), 2.61 (1 H, dq, J 2.4, 6.8,

802 (M⁺+ 1, 5).

2-H or 2′-H), 2.87 (3 H, br. s, NCH₃), 3.13 and 3.45 (each 1 H, m),

(2S,3R,6S,8S)-8-{(2R,3R,6S,7S,8S,9S,10R,13S,15R)-3,6;10,13-^BIS- 3.65 (1 H, dt, J 3.9, 10.3), 3.78, 3.89, 4.00 and 4.21 (each 1 H,

E^POXY-15-(N-TERT-BUTYLOXYCARBONYL-N-METHYLAMINO)-8-HYDROXY-2,7,9- m), 4.30 (1 H, br. m, NH), 4.90 (1 H, d, J 10.6, 8-H), 4.92 (1 H,

TRIMETHYLOCTADECANOYLOXY}-3,6-EPOXY-2-METHYLUNDECANOIC

ACID m, 8′-H); m/z (ES⁺) 594 (M⁺+ 1, 100%). This was taken up in

(94). Palladium (10% wt. on activated carbon, 8 mg) was acetonitrile (0.2 mL) and formalin (0.3 mL, 0.01 mmol) and

added to the benzyl ester 93 (44 mg, 0.055 mmol) in ethanol sodium cyanoborohydride (3.8 mg, 0.060 mmol) were added.

(2 mL) and the suspension stirred under an atmosphere of The mixture was stirred at room temperature for 1.5 h, acetic

hydrogen for 16 h. The mixture was filtered through celite® acid (6 μL, 0.11 mmol) was added and the mixture was stirred

and the residue washed with ethanol (10 mL). Concentration an additional 21 h. Ether (5 mL) and saturated aqueous

Org. Biomol. Chem., 2012, 10, 9709–9733 | 9731

Paper

sodium carbonate (5 mL) were added and the mixture stirred

for 15 min before being extracted with ether (3 × 2.5 mL), DCM

(3 × 2.5 mL) and ethyl acetate (2.5 mL). The organic extracts

were combined, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography using hexane : ethyl acetate

(8 : 1.5 with triethylamine 5%) gave the title compound 1

(4.6 mg, 70%) as a clear viscous oil, [α]²_D⁵+13.3 (c 0.3 in

CHCl₃), lit.^1a+22.8 (c 0.26 in MeOH); δ_H(400 MHz, acetone-d₆

– TFA,) 0.85 (6 H, d, J 6.6, 7-CH₃and 9-CH₃), 0.87 (3 H, t, J 7.3,

11′-H₃), 1.04 (3 H, t, J 7.3, 18-H₃), 1.05 (3 H, d J 6.8, 2′-CH₃),

1.09 (3 H, d J 7.1, 2-CH₃), 1.24–2.08 (26 H, m), 2.27 (1 H, dq, J

10.0. 7.2, 2-H), 2.75 (1 H, dq, J 2.0, 7.0, 2′-H), 2.98 and 3.22

(each 3 H, t, J 2.5, NCH₃), 3.38 (1 H, m, 10-H), 3.62 (1 H, m, 15-

H), 3.72 (1 H, dt, J 10.8, 4.0, 3-H), 3.81–3.93 (2 H, m, 13-H, 6′-

H), 4.10 (1 H, ddd, J 9.2, 6.8, 2.0, 3′-H), 4.29 (1 H, m, 6-H), 4.92

(1 H, m, 8′-H) and 4.98 (1 H, dd, J 11.2, 1.2, 8-H); m/z (ES⁺) 608

(M⁺+ 1, 100); δ_C(125 MHz, acetone-d₆– TFA,) 8.7 (12′-C), 9.8

(20-C), 10.4 (21-C), 14.0 (2; 18-C and 19-C), 14.3 (11′-C), 18.8

(10′-C), 20.3 (17-C), 27.9 (4′-C), 28.1 (5-C), 29.0 (16-C), 30.0 (11-

C), 31.1 (4-C), 31.6 (12-C), 32.1 (5′-C), 34.2 (14-C), 36.5 (22-C),

37.9 (2; 9′-C and 7-C), 39.4 (7′-C), 41.5 (9-C), 42.1 (2′-C), 43.7

(23-C), 47.9 (2-C), 68.7 (15-C), 71.5 (8′-C), 75.2 (2; 8-C and 6′-C),

77.3 (6-C), 79.2 (3′-C), 80.0 (13-C), 81.1 (10-C), 83.2 (3-C), 173.7

(1′-C) and 175.0 (1); m/z (EI) 607 (M⁺, 5%), 564 (30) and 100

(100).

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Acknowledgements

We sincerely thank Professor M. Natsume of the Department

of Applied Biological Science in the Tokyo University of Agri-

culture and Technology for help in confirming the structure of

synthetic pamamycin 607 by generously providing a sample of

the natural product and copies of spectra. We should also like

to thank Dr P. Evans (now at University College, Dublin) for

carrying out the last two steps in the synthesis of pamamycin

607 and the EPSRC Mass Spectrometric Service at Swansea for

high resolution mass spectra. We should also like to thank the

EPSRC for support (to N. K.).

Notes and references

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9732 | Org. Biomol. Chem., 2012, 10, 9709–9733

Organic & Biomolecular Chemistry