Polyketide synthesis using the boron-mediated, anti-aldol reactions of lactate-derived ketones: Total synthesis of (-)-ACRL toxin IIIB

SYNTHESIS

April 1998

639

Polyketide Synthesis Using the Boron-Mediated, anti-Aldol Reactions of Lactate-

Derived Ketones: Total Synthesis of (–)-ACRL Toxin IIIB

Ian Paterson,* Debra J. Wallace, Cameron J. Cowden

University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK

Fax +(44)1223 336362; E-mail: ip100@cus.cam.ac.uk; Website: http://ip07.ch.cam.ac.uk/

Received 29 August 1997; revised 12 September 1997

Abstract: The boron-mediated, anti-selective, aldol reactions of

ketone 2 (and related derivatives) proceed with high levels of

asymmetric induction, diastereoselectivities of up to 200:1 in

favour of the aldol adducts 4 are obtained with achiral aldehydes

and reagent control operates with chiral aldehydes. These lactate-

derived ketones provide a versatile chiral auxiliary for the synthe-

sis of β-hydroxy carbonyl compounds. Oxidative removal of the

auxiliary provides enantiomerically pure aldehydes 5, while

reductive deoxygenation gives the corresponding ethyl ketones 6.

This practical asymmetric methodology for generating anti-aldols

is illustrated by an efﬁcient total synthesis of (–)-ACRL toxin IIIB

(7), which proceeds in 15 steps from 2 with 21% overall yield and

88% diastereoselectivity.

Key words: chiral auxiliary, lactate, enol borinate, anti-aldol,

(–)-ACRL toxin IIIB

The polyketides represent an important reservoir of natu-

ral product diversity, which is associated with a wide

range of biological activity. These polyoxygenated com-

Figure

pounds continue to stimulate the development of new syn-

thetic methods and strategies, particularly for the

installation of the characteristic stereochemical arrays of

alternating methyl and hydroxyl groups. Asymmetric al-

the resulting adducts, make this method advantageous. Fi-

nally, we illustrate this novel aldol methodology by its ap-

plication to the total synthesis of (–)-ACRL toxin IIIB (7),

as a representative polyketide derivative having anti-con-

figured propionate units.⁹

Synthesis of 2: Our initial multi-step synthesis⁴of the eth-

yl ketone 2 via the corresponding benzyl ether 3 has been

superseded by a shorter, more convenient route. Both

enantiomers of ketone 2 are now readily available in three

routine steps (65% overall) from the commercially avail-

able lactate esters (Scheme 1). Ethyl (S)-(–)-lactate was

first reacted with N,O-dimethylhydroxylamine hydro-

chloride, in the presence of i-PrMgCl, to give the Weinreb

amide (S)-8 in 85% yield. This improved procedure¹¹is

dol reactions, which can combine the formation of car-

bon-carbon bonds with the generation of two stereogenic

centres, have emerged as especially powerful tools for the

efficient synthesis of polyketides.¹In particular, the use of

a temporary chiral auxiliary attached to a stereodefined

enolate is a popular tactic, with removal of the auxiliary

after the aldol step. However, while such syn-selective

asymmetric aldol reactions can be used with confidence,

the analogous anti-selective transformation is generally

much less straightforward.^1,2

We have previously developed the use of β-alkoxy ke-

tones such as 1 (Figure), where high levels of π-face se-

lectivity can be readily achieved in both syn- and anti-

selective aldol reactions by appropriate choice of the met-

al enolate derivative.³As a recent extension, we intro-

duced the related α-alkoxy ketones 2 and 3 for boron-

mediated aldol reactions, where the simple choice of hy-

droxyl protecting group determines the enolate geometry

and resulting syn vs anti diastereoselectivity.^4–6Hence,

these lactate-derived, chiral ketones^7,8function as versa-

tile new reagents for stereocontrolled polyketide synthe-

sis.^9,10

We now report our preferred synthesis of ketone 2 and

provide full details of its anti-selective, asymmetric aldol

reactions with aldehydes. The resulting aldol adducts 4

can be elaborated into a wide range of enantiomerically

pure carbonyl compounds, e.g. by transformation into al-

dehydes 5 and ethyl ketones 6. The ready availability of

the auxiliary group, the general efficiency and mildness of

the boron-mediated aldol reaction, and the versatility of

Scheme 1

SYNTHESIS

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640

experimentally straightforward and avoids the use of py- In each case, the stereoselectivity of the aldol reaction was

rophoric Me₃Al. Addition of EtMgBr to (S)-8, followed determined by HPLC and/or ¹H NMR (400 MHz) analysis

by benzoylation of the resulting (volatile) α-hydroxy ke- of the crude reaction mixture. A single recrystallisation

tone with benzoic anhydride (Bz₂O), then provided (S)-2, usually sufficed to give the stereochemically homoge-

[α]_D²⁰+25.1 (c = 4.6, CHCl₃). In an identical manner, neous aldol adduct. The relative and absolute configura-

isobutyl (R)-(+)-lactate was converted into (R)-2 via the tions of the aldol adducts 4a–e were assigned by various

enantiomeric amide (R)-8. A variety of related alkyl ke- means. The 1,2-anti relationship was ascertained from the

tones, e.g. (R)-9, can be prepared in enantiomerically pure diagnostic large vicinal coupling constant, J_1,2= 7.0–

form by suitable choice of Grignard or organolithium re- 8.8 Hz (cf. J_1,2= 3–5 Hz for the syn-aldol isomers). The

agents. These ketones are configurationally stable and can absolute configuration at the new secondary hydroxyl

be stored for extended periods.

centre was determined using the advanced Mosher

1

method¹³through comparison of the relevant H NMR

anti-Selective, Asymmetric Aldol Reactions of 2: From ex-

perience already gained with the anti-aldol reactions of

ethyl ketone 1,³we sought to achieve selective enolisation

of 2 to generate the corresponding (E)-enol dicyclohex-

ylborinate 10 (Scheme 2). This can be achieved¹²using

Brown's dicyclohexylboron chloride (c-Hex₂BCl), as a

chemical shifts of the diastereomeric (R)- and (S)-MTPA

esters. The enantiomeric purity of the aldol products was

assessed as >97% ee by ¹⁹F NMR spectroscopy of these

same Mosher esters, indicating that no racemisation had

occurred.

mild Lewis acid, in conjunction with a sterically unde- The high levels of selectivity obtained with these simple

manding, tertiary amine base. Indeed, the optimal con- aldehydes led us next to examine reagent control in aldol

ditions for the anti-aldol reaction of 2 were enolisation by additions to chiral aldehydes (Scheme 3). Following eno-

c-Hex₂BCl and Me₂NEt in Et₂O at 0°C for 2 hours to gen- lisation of ketone (S)-2, the derived (E)-enol borinate 10

erate 10 in situ, prior to cooling to –78°C, and addition of was reacted separately with the enantiomeric aldehydes

the required aldehyde. Storing the reaction mixture at (S)- and (R)-11, leading to the formation of adducts 12 and

–26°C (freezer) over a period of 14 hours ensured com- 13 with > 97% ds (matched) and 92% ds (mismatched),

plete conversion, whilst maintaining high levels of selec- respectively. This latter result indicates that the high π-fa-

tivity, before normal oxidative workup (H₂O₂, pH 7 cial selectivity of the enolate 10 overrides the Felkin–Anh

buffer). As shown in Table 1, this procedure led to high type induction from the aldehyde, which bodes well for

yields for a range of aliphatic, aromatic and unsaturated general application in the stereocontrolled synthesis of

aldehydes, accompanied by excellent diastereoselectivi- complex polyketide systems. All of these auxiliary-con-

ties. The crystalline 1,2-anti-2,4-anti adducts 4a–e were trolled aldol reactions employ c-Hex₂BCl as a mild eno-

isolated in 85–97% yield with ≥ 95% ds.

lising reagent, which is easy to prepare¹²as well as being

commercially available. Under the conditions of the aldol

reaction, this reagent is compatible with most functional

groups and can be used with sensitive aldehydes.^10,14,15

Scheme 2

Table 1. anti-Aldol Reactions of (S)-2 with RCHO^a

RCHO

R

Product^b

ds^c

Yield^d

(%)

i-Pr

Ph

Et

4a

4b

4c

4d

4e

97:3

95

85

82

97

85

99.5:0.5

98:2

CH₂=C(Me)

(E)-MeCH=CH

95:5

a

Reaction conditions: c-Hex₂BCl/Me₂NEt/Et₂O, 0°C, 2 h; RCHO,

–78 → –26°C, 14 h.

Enantiomeric purity (> 97% ee) and hydroxyl configuration deter-

mined by ¹⁹F and ¹H NMR analysis of (R)- and (S)-MTPA esters.

Ratio of major isomer to sum of minor isomers by HPLC.

Isolated yield of aldol adducts after chromatography.

b

c

d

Scheme 3

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641

The origin of the high levels of π-face selectivity in the re-

actions of 10 can be traced to the relative steric and elec-

tronic contributions of the substituents (H, Me, OBz) at

the enolate stereocentre in the chair transition state for the

aldol addition (Scheme 4).¹⁶For such (E)-enol borinates,

there is a strong preference for the proton to eclipse the

double bond to minimise A(1,3) allylic strain. In the com-

peting transition structures, TS-I and TS-II, the benzoate

group is directed either inwards or outwards in the chair

arrangement. In TS-II (re-face attack on aldehyde), there

is likely to be a destabilising lone-pair repulsion between

the benzoate and enolate oxygens. Based on the formyl

hydrogen bond model recently espoused by Corey et al.¹⁷

to explain the facial selectivity in a number of asymmetric

addition processes, TS-I (si-face attack on aldehyde) may

be favoured due to a stabilising H-bond between the ben-

zoate oxygen with the aldehyde proton. Taken together,

this analysis accounts for the apparent contra-steric pref-

erence for the benzoate to occupy the inside position.

Scheme 5

synthetic approaches to zaragozic acid C¹⁰and concana-

mycin A.¹⁴

Manipulation of the Aldol Adducts: These anti-aldol ad-

ducts can be transformed into a range of useful intermedi-

ates for the synthesis of polyketide natural products. As

shown in Scheme 6, the most widely used transformation

is to give the α-methyl-β-siloxy aldehydes 5.^5,10This can

be accomplished in a high yielding, three-step sequence

(Table 2).

Scheme 6

Table 2. Preparation of Aldehydes 5^a

Aldol

Adduct

R

Product^b

Yield^c

(%)

4a

4b

4e

12

13

i-Pr

Ph

5a

5b

5c

5d

5e

74

85

82^d

70

83

(E)-MeCH=CH

(S)-BnOCH₂CH(Me)

(R)-BnOCH₂CH(Me)

Scheme 4

a

Reaction conditions as in Scheme 6 unless otherwise stated.

Diastereomeric purity (> 99%) by HPLC analysis and H NMR

b

1

In addition to these results for ethyl ketone 2, comparable

stereoselectivities can also be obtained in the boron-medi-

ated, anti-aldol reactions of related ketones (Scheme 5).

For example, addition of the propyl ketone (R)-9 to isobu-

tyraldehyde gave 14 in 95% yield with 93% ds. In an anal-

ogous manner to 2, the alkoxymethyl ketone 15 was

cleanly enolised by c-Hex₂BCl and Me₂NEt to give the

enol borinate 16, which gave the corresponding anti aldol

adduct 17 on addition to isobutyraldehyde, with high lev-

els of asymmetric induction (≥ 99% ds). These more high-

ly oxygenated ketones should prove useful for the

asymmetric synthesis of contiguous polyols. In other stud-

ies from our laboratory, they have already been used in

spectroscopy.

c

Isolated overall yield after chromatography.

NaBH₄reduction followed by K₂CO₃hydrolysis was used.¹⁸

d

First, silylation of 4 with tert-butyldimethylsilyl triflate

(TBSOTf) gave the corresponding silyl ether 18. Subse-

quently, ketone reduction with LiBH₄was accompanied

by cleavage of the benzoate group, 18 → 19, which (al-

though not essential here) proceeded with good levels of

diastereoselectivity (≥ 90 ds). Alternatively, NaBH₄re-

duction followed by K₂CO₃hydrolysis of the benzoate

also gave the 1,2-diol 19 in high yield. In several cases,

SYNTHESIS

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642

the predominating 1,2-diol stereochemistry in 19 was de-

termined by appropriate NOE analysis of the derived cis-

acetonide. While the reduction stereoselectivity here can

be influenced to varying extents by the substituents on ei-

ther side of the ketone, it appears largely to arise by Fel-

kin–Anh control associated with the sterically demanding

TBS-containing residue.¹⁹The resulting monoprotected

1,2,4-triols 19 have four contiguous stereocentres, which

may be exploited if required. For our present purposes,

two of these stereocentres are discarded in the next step,

whereby glycol cleavage with NaIO₄gave the aldehydes

5.

As an alternative to this oxidative cleavage sequence, re-

ductive removal²⁰of the α−benzoate substituent in 18 by

SmI₂gave a high yield of the corresponding ethyl ketones

6a and 6b (Scheme 7). Notably, this asymmetric synthesis

of diethyl ketone anti-aldol adducts is experimentally

convenient and complements alternative routes using

chiral boron reagents.¹By using a second aldol reaction

on the ethyl side, such ketones permit the highly stereo-

controlled synthesis of elaborate polypropionate sys-

tems.^15,21

Scheme 7

Total Synthesis of (–)-ACRL Toxin IIIB: The phytopatho-

genic fungus Alternaria citri, which causes brown spot

disease of citrus, produces several host specific toxins

(Scheme 8) that damage the leaves of rough lemon and

Rangpur lime plants. The major component, ACRL toxin

IA (20), is the most active toxin, with ACRL toxin IIIA

(21) being isolated in smaller quantities, along with other

minor components.²²Full structural characterisation of

the toxins was only possible from their methyl ether deriv-

atives ACRL toxin IB (22) and IIIB (7). We were attracted

to these fungal polyketides as synthetic targets²³due to the

two anti-configured propionate units present in the side

chain. As already mentioned, these are generally more dif-

ficult to control than the corresponding syn-relationships.

As such, ACRL toxin IIIB (7) was selected to demonstrate

the utility of our new anti-aldol methodology.

Scheme 8

dol reaction between ethyl ketone (S)-2 and tiglic alde-

hyde (25). Under standard conditions, the reaction

proceeded with excellent diastereoselectivity (≥99% ds)

and, following a single recrystallisation, the aldol adduct

28 was obtained in 86% yield. HPLC analysis of the crude

product indicated that < 1% of other isomers were pro-

duced. This β-hydroxy ketone was then converted into al-

dehyde 24 (88%) via the usual three-step sequence of

protection, reduction and oxidative cleavage. Next, chain

extension by a Ba(OH)₂-promoted HWE reaction²⁴gave

solely the (E)-alkene 29 (83%). The use of stronger bases

led to some epimerisation at C₁₂, as well as traces of the

(Z)-alkene. Subsequent DIBAL reduction of this ester,

followed by Dess–Martin oxidation,²⁵gave the enal 23

(93%). In an analogous manner, the anti-aldol reaction of

(S)-2 with enal 23 gave the adduct 30 (95%). As before,

¹H NMR and HPLC analysis indicated ≥99% ds. Repeat-

ing the highly reproducible, three-step sequence then gave

the aldehyde 26 (84%). This aldol-based synthesis is no-

Our retrosynthetic analysis (Scheme 8) is based on three

disconnections which, in the forward sense, involve the

control of stereochemistry in addition reactions to alde-

hydes. We planned to use the ketone (S)-2 to control both

the stereochemistry at C₈–C₉and C₁₂–C₁₃via anti-aldol

additions to aldehyde 23 (derived from 24) and tiglic alde-

hyde (25), respectively. The final coupling step planned

between aldehyde 26 and α-pyrone 27, while having some

precedent in a previous synthesis of ACRL toxin IIIB by

Mulzer et al.,^23apresented greater uncertainty in the sense

and degree of stereoinduction.

As shown in Scheme 9, the C₁₂and C₁₃stereocentres

were first installed together by a boron-mediated, anti-al-

SYNTHESIS

April 1998

643

Scheme 10

Scheme 9

table for achieving essentially complete control of the four

stereocentres in the ACRL toxin side chain and proceeds

in 46% yield from ketone (S)-2.

As shown in Scheme 10, completion of the synthesis re-

quired the C₆–C₇coupling between aldehyde 26 and the

commercially available α-pyrone 27. In order to generate

the correct configuration at C₇, addition of the metallated

α-pyrone 27 is required to occur on the opposite face of

the α-chiral aldehyde to that normally predicted by

the Felkin–Anh model. Although there was some

precedent^23afor this, in our hands, deprotonation of α-py-

rone 27 (KHMDS, Et₂O, –100°C) and addition of 26

gave, at best, a 71 : 29 ratio of adducts. Following HPLC

separation, the major product 31 was isolated in 48% yield

along with 19% of 7-epi-31. Subsequent deprotection of

31 and recrystallisation gave pure (–)-ACRL toxin IIIB

(7) in 79% yield.

In an attempt to improve the product distribution resulting

from the modestly selective pyrone addition, we chose to

explore the reduction of the C₇ketone. The mixture of

epimeric alcohols at C₇was oxidised with Dess–Martin

periodinane²⁵to give ketone 32 (91%). Conversion of this

ketone to the correct alcohol 31 now required selective

hydride addition in the Felkin–Anh sense. While NaBH₄

or DIBAL both led to predominant formation of 31, the

selectivity obtained was disappointing (ca. 2:1).

Scheme 11

ketone 33. Removal of the two silyl protecting groups

from ketone 32 was achieved with HF•pyridine to give 33

(74%). Precomplexation with Bu₂BOMe,²⁶followed by

reduction of the intermediate boron chelate 34 with

LiBH₄then led to a 94% yield of ACRL toxin IIIB (7) and

1

its C₇epimer. Analysis of the 400 MHz H NMR spec-

trum showed that the ratio of alcohols was now much im-

A more rewarding strategy (Scheme 11) was to exploit the

chelation controlled, 1,3-syn reduction of the β-hydroxy

SYNTHESIS

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644

HRMS (CI, NH₃): m/z [M+H]⁺found 134.0817, C₅H₁₂O₃N requires

134.0817.

proved at 89 : 11. A single recrystallisation gave pure (–)-

ACRL toxin IIIB (7), obtained in 82% isolated yield,

1

LRMS (CI, NH₃): m/z = 34 ([M+H]⁺, 100).

which had H and ¹³C NMR data in full agreement with

that reported for the authentic compound. The specific ro-

tation recorded for 7, [α]_D²⁰–47.0 (c = 0.6, CHCl₃), was in

good agreement with that obtained by Mulzer et al.,

[α]²⁰_D–49.0 (c = 0.8, CHCl₃). This improved synthesis of

(–)-ACRL toxin IIIB proceeds in 15 steps with 21% over-

all yield and an acceptable 88% diastereoselectivity for

the installation of the five stereocentres.

(S)-2-Benzoyloxypentan-3-one [(S)-2]; Typical Procedure:

To a cooled (0°C) solution of amide (S)-8 (1.0 g, 7.5 mmol) in THF

(30 mL) was added a 3 M solution of EtMgBr in Et₂O (8 mL) and the

reaction mixture was allowed to warm to r.t. After 1 h, satd aq NH₄Cl

solution (40 mL) was added and the mixture was extracted with Et₂O

(20 mL) followed by CH₂Cl₂(2 × 20 mL). The combined organic ex-

tracts were dried (MgSO₄) and concentrated to ca. 50 mL. To this so-

lution was added Bz₂O (2.55 g, 11.3 mmol), DMAP (0.10 g,

0.82 mmol) and i-Pr₂NEt (2.5 mL, 14.3 mmol). After stirring for 14

h, excess Bz₂O was removed by addition of ethylenediamine (0.5 g,

8.3 mmol). H₂O (40 mL) was added, the mixture extracted with Et₂O

(4 x 20 mL), then the organic extracts were dried (MgSO₄) and con-

centrated to an oil. Column chromatography (20% EtOAc in hexane)

Conclusions: The boron-mediated, anti-aldol chemistry

of ketone 2 enables the efficient asymmetric synthesis of

a wide range of valuable polyketide intermediates, as il-

lustrated here by its application to the total synthesis of

(–)-ACRL toxin IIIB (7). Key features of this method are:

(i) the use of an auxiliary from readily available (R)- or

(S)-lactate; (ii) the ability to introduce other α-substitu-

ents; and (iii) the operation of reagent control from the

enolate in additions to chiral aldehydes. The subsequent

manipulation of the aldol products to give aldehydes and

ethyl ketones demonstrates the use of the lactate-derived

HCMe(OBz) group as a versatile chiral auxiliary. More-

over, this stereoinducing group should be considered as an

optional auxiliary for asymmetric synthesis, which may

be retained if desired. For example, the reduction of ke-

tones 18 with LiBH₄provides useful monoprotected

1,2,4-triols 19 having four contiguous stereocentres.

afforded (S)-2 (1.18 g, 76%) as a colourless oil; [α] +25.1 (c = 4.6,

D

CHCl₃).

IR (film) ν = 1718 (s), 1601 cm^–1(w).

¹H NMR (400 MHz): δ = 1.05 (t, 3 H, J = 7.4 Hz, CH₂CH₃), 1.52 [d,

3 H, J = 7.0 Hz, CH(CH₃)OBz], 2.56 (dq, 1 H, J = 14.6, 7.4 Hz,

CH_AH_BCH₃), 2.64 (dq, 1 H, J = 14.6, 7.4 Hz, CH_AH_BCH₃), 5.33 [q,

1 H, J = 7.0 Hz, CH(CH₃)OBz], 7.52 ( t, 2 H, J = 6.8 Hz, ArH), 7.58

(tt, 1 H, J = 6.8, 1.2 Hz, ArH), 8.07 (dd, 2 H, J = 6.8, 1.2 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 7.4, 16.7, 31.7, 75.3, 128.6, 129.6, 130.0,

133.6, 166.1, 208.7.

HRMS (CI, NH₃): m/z [M+H]⁺found 207.1021, C₁₂H₁₅O₃requires

207.1021.

LRMS (CI, NH₃): m/z 207 ([M+H]⁺100), 105 (30).

Analysis: found C, 70.18; H, 6.88; C₁₂H₁₄O₃requires C, 69.88; H, 6.84.

In a related manner, following the typical procedure for the prepara-

tion of 2, the ketones (R)-9 and 15 were obtained using PrMgBr and

BnOCH₂Li/MgBr₂, respectively, in the reactions.

This new anti-selective aldol methodology, combined

with the related syn-selective transformations using the

analogous benzyl ether 3,^4–6should have general utility

for the synthesis of a variety of polyketide natural prod-

ucts.

(R)-2-Benzoyloxyhexan-3-one [(R)-9]:

R (40% Et₂O in hexane) 0.48; [α] –12.8 (c = 0.8, CHCl₃).

f

D

IR (film): ν = 1719 (s), 1609, 1595 cm^–1(w).

¹H NMR spectra were recorded at either 250, 400 or 500 MHz on

Bruker AC and DPX250, AM400 or DRX500 spectrometers and ¹³C

spectra were recorded at either 62.9 or 100.6 MHz on Bruker AC and

DPX250 or AM400 spectrometers. All spectra were obtained using

CDCl₃as solvent and referenced to CHCl₃(δ = 7.26) for ¹H NMR and

CDCl₃(δ = 77.0) for ¹³C NMR. The numbering of carbon atoms for

assignment refers to the numbering of the carbon skeleton of the tar-

get product 7. Optical rotations were measured at 20°C. Except for

aqueous reactions, all experiments were carried out under an argon at-

mosphere with anhydrous solvents. Silica gel was used to perform the

column chromatography. The following solvents and reagents were

purified and dried according to recommended procedures: THF,

Et₂O, CH₂Cl₂, Me₂NEt, 2,6-lutidine and i-Pr₂NEt.²⁷

¹H NMR (400 MHz): δ = 0.92 (t, 3 H, J = 7.2 Hz, CH₂CH₂CH₃), 1.52

[d, 3 H, J = 7.1 Hz, CH(CH₃)OBz], 1.66 (sextet, 2 H, J = 7.2 Hz,

CH₂CH₂CH₃), 2.47 (dt, 1 H, J = 17.4, 7.2 Hz, CH_AH_BCH₂CH₃), 2.59

(dt, 1 H, J = 17.4, 7.2 Hz, CH_AH_BCH₂CH₃), 5.32 [q, 1 H, J = 7.1 Hz,

CH(CH₃)OBz], 7.46 (dd, 2 H, J = 7.9, 7.3 Hz, ArH), 7.59 (tt, 1 H, J =

7.3, 1.6 Hz, ArH), 8.07 (dd, 2 H, J = 7.9, 1.6 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 13.7, 16.3, 16.7, 40.1, 75.2, 128.5, 129.6,

129.8, 133.4, 165.9, 207.9.

HRMS (+FAB): m/z [M+H]⁺found 221.1170, C₁₃H₁₇O₃requires

221.1178.

LRMS (+FAB): m/z = 221 ([M+H]⁺, 60), 154 (26), 105.

(S)-3-Benzoyloxy-1-benzyloxybutan-2-one [(S)-(15)]:

R (CH₂Cl₂) 0.24; [α] +23.8 (c = 1.4, CHCl₃).

f

D

IR (film): ν =1712 (s), 1602, 1584, 1558 cm^–1(w).

(S)-2-Hydroxy-N-methoxy-N-methylpropionamide [(S)-8]:

To a cooled (–20°C) mixture of ethyl (S)-lactate (2.0 g, 16.9 mmol)

and MeON(Me)H•HCl (4.1 g, 42 mmol) in THF (50 mL), was added

a 2 M solution of i-PrMgCl in Et₂O (42 mL) dropwise over 30 min.

The reaction mixture was stirred at –20°C for 30 min and at 0°C for

a further 30 min before satd aq NH₄Cl solution (150 mL) was added.

The mixture was extracted with Et₂O (4 × 50 mL), followed by

CH₂Cl₂(4 x 50 mL). The combined organic extracts were dried

(MgSO₄), concentrated in vacuo, and the residue purified by column

chromatography (50% EtOAc in hexanes → EtOAc) to give the

amide 8 (1.91 g, 85%) as a colourless oil. On a larger scale, purifica-

¹H NMR (250 MHz): δ = 1.57 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz],

4.28 (d, 1 H, J = 15.1 Hz, CH_AH_BOBn), 4.37 (d, 1 H, J = 15.1 Hz,

CH_AH_BOBn), 4.61 (d, 1 H, J = 11.7 Hz, OCH_AH_BPh), 4.65 (d, 1 H, J

= 11.7 Hz, OCH_AH_BPh), 5.54 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz],

7.37–7.25 (m, 5H, ArH), 7.45 (dd, 2 H, J = 8.2, 7.0 Hz, ArH), 7.58 (tt,

1 H, J = 7.0, 1.4 Hz, ArH), 8.04 (dd, 2 H, J = 8.2, 1.4 Hz, ArH).

¹³C NMR (62.9 MHz): δ = 16.2, 72.7, 73.3, 128.0, 128.1, 128.5,

129.3, 129.8, 133.4, 137.0, 165.9, 205.2.

HRMS (CI, NH₃): m/z [M+H]⁺found 299.1283, C₁₈H₁₉O₄requires

299.1283.

LRMS (CI, NH₃): m/z 316 ([M+NH₄]⁺, 53), 299 ([M+H]⁺, 64), 208

(50), 196 (100).

tion was achieved by distillation; bp 63–65°C/0.5 Torr; [α] –50.0

D

(c = 2.2, CHCl₃).

IR (film): ν = 3440 (br), 1658 cm^–1(s).

¹H NMR (400 MHz): δ = 1.33 [d, 3 H, J = 6.7 Hz, CH(CH₃)OH], 3.22

(s, 3 H, NCH₃); 3.35 (d, 1H, J = 6.7 Hz, OH), 3.69 (s, 3 H, OCH₃),

4.47 [qn, 1H, J = 6.7 Hz, CH(CH₃)OH].

anti-Aldol Reaction of (S)-2 Using c-Hex₂BCl; Synthesis of 4a–e,

12–14, 17, 28 and 30; General Procedure A:

To a cooled (–78°C) solution of c-Hex₂BCl (0.16 g, 0.75 mmol) in

Et₂O (2 mL) was added Me₂NEt (96 mg, 0.9 mmol), followed by ke-

¹³C NMR(100.6MHz):δ=20.8,32.2,61.1,64.7,175.6.

SYNTHESIS

April 1998

645

tone (S)-2 (0.10 g, 0.5 mmol) in Et₂O (2 mL). The reaction mixture

was warmed to 0°C and stirred for 2 h before recooling to –78°C. The

required aldehyde (2.0 mmol for achiral aldehydes) was added and

the stirring continued for a further 2 h, before being transferred to the

freezer (–26°C) for 14 h. The reaction was quenched at 0°C by addi-

tion of MeOH (2 mL) and pH 7 buffer (2 mL), H₂O₂(2 mL, 30%) was

then added and the stirring continued for 1 h. The mixture was parti-

tioned between H₂O (30 mL) and CH₂Cl₂(3 × 30 mL). The combined

organic extracts were dried (MgSO₄) and concentrated in vacuo. Iso-

lation of the aldol products was achieved by column chromatography

and diastereomeric ratios determined by 400 MHz ¹H NMR analysis

and/or HPLC separation. The yields and diasteromeric ratios for 4a–e

are given in Table 1.

LRMS (+FAB): m/z = 265 ([M+H]⁺, 60), 154 (100), 136 (95), 105

(80), 71 (45).

(2S,4R,5S)-2-Benzoyloxy-5-hydroxy-4,6-dimethylhept-6-en-3-one

(4d):

R (50% Et₂O in hexane) 0.35; mp 59–60°C; [α] +29.0 (c = 0.6

f

D

CHCl₃).

IR (CHCl₃): ν = 3509 (br), 1718 (s), 1601 cm^–1(w).

¹H NMR (400 MHz): δ = 1.03 [d, 3 H, J = 7.2 Hz, CH(CH₃)CHOH],

1.56 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz], 1.71 [s, 3 H, C(=CH₂)CH₃],

2.28 (br s, 1 H, OH), 3.01 [dq, 1 H, J = 8.8, 7.2 Hz, CH(CH₃)CHOH],

4.25 (d, 1 H, J = 8.8 Hz, CHOH), 4.92 (s, 1 H, =CH_AH_B), 4.95 (s, 1

H, =CH_AH_B), 5.44 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz], 7.44 (t, 2 H, J

= 7.4 Hz, ArH) 7.56 (t, 1 H, J = 7.4 Hz, ArH), 8.07 (d, 2 H, J = 7.4

Hz, ArH).

(2S,4R,5R)-2-Benzoyloxy-5-hydroxy-4,6-dimethylheptan-3-one (4a):

R (50% Et₂O in hexane) 0.39; mp 93–94°C; [α] +41.6 (c = 1.0,

¹³C NMR (100.6 MHz): δ = 14.5, 15.6, 16.6, 45.5, 75.0, 78.3, 114.5,

128.5, 129.6, 129.8, 133.3, 144.4, 165.9, 211.0.

f

D

CHCl₃).

HRMS (+FAB): m/z [M+H]⁺found 277.1413, C₁₆H₂₁O₄requires

277.1440.

1

IR (CHCl₃): ν = 3545 (br), 1733 (s), 1699 (s), 1601, 1584, 1492 cm^–

(w).

LRMS (+FAB): m/z = 277 ([M+H]⁺, 78), 154 (100), 136 (80), 105

(70).

¹H NMR (400 MHz): δ = 0.87 [d, 3 H, J = 6.8 Hz, CH(CH₃)CH₃],

0.94 [d, 3 H, J = 6.8 Hz, CH(CH₃)CH₃], 1.20 [d, 3 H, J = 7.2 Hz,

CH(CH₃)CHOH], 1.55 [d, 3 H, J = 7.1 Hz, CH(CH₃)OBz], 1.77 [sep-

tet d, 1 H, J = 6.8, 4.1 Hz, CH(CH₃)₂], 2.33 (d, 1 H, J = 6.4 Hz, OH),

2.99 [br quintet, 1 H, J = 7.2 Hz, CH(CH₃)CHOH], 3.57 (ddd, 1 H, J

= 7.2, 6.4, 4.1 Hz, CHOH), 5.43 [q, 1 H, J = 7.1 Hz, CH(CH₃)OBz],

7.43 (dd, 2 H, J = 7.9, 7.6 Hz, ArH), 7.57 (t, 1 H, J = 7.6 Hz, ArH),

8.05 (d, 2 H, J = 7.9 Hz, ArH).

(2S,4R,5R,6E)-2-Benzoyloxy-5-hydroxy-4-methyloct-6-en-3-one

(4e):

R (50% Et₂O in hexane) 0.30; mp 130–132°C; [α] +34.6 (c = 0.5,

f

D

CHCl₃).

IR (CHCl₃): ν = 3416 (br), 1732 (s), 1718 cm^–1(s).

¹H NMR (400 MHz): δ = 1.17 [d, 3 H, J = 7.2 Hz, CH(CH₃)CHOH],

1.55 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz], 1.69 (dd, 3 H, J = 6.4, 1.4

Hz, =CHCH₃), 2.24 (br, s, 1 H, OH), 2.88 [qn, 1 H, J = 7.2 Hz,

CH(CH₃)CHOH], 4.20 (dd, 1 H, J = 7.8, 7.2 Hz, CHOH), 5.46–5.39

[m, 2 H, =CH(CH)OH and CH(CH₃)OBz], 5.72 (dq, 1 H, J = 15.2, 6.4

Hz, =CHCH₃), 7.46 (dd, 2 H, J = 7.4, 8.0 Hz, ArH), 7.57 (tt, 1 H, J =

7.4, 1.3 Hz, ArH), 8.07 (dd, 2 H, J = 8.0, 1.3 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 14.5, 15.9, 17.7, 48.2, 74.9, 75.0, 128.5,

129.3, 129.6, 129.8, 131.4, 133.3, 165.9, 211.3.

¹³C NMR (100.6 MHz): δ = 14.4, 15.2, 15.9, 20.0, 29.8, 54.5, 74.8,

77.7, 128.5, 129.5, 129.8, 133.3, 165.9, 212.0.

HRMS (CI, NH₃): m/z [M+H]⁺found 279.1596, C₁₆H₂₃O₄requires

279.1596.

LRMS (CI, NH₃): m/z = 279 ([M+H]⁺,100), 261 (32), 207 (100), 159

(64), 141 (43), 105 (60).

Analysis: found C, 69.10; H, 7.82; C₁₆H₂₂O₄requires C, 69.04; H,

7.94.

HRMS (+FAB): m/z [M+H]⁺found 277.1447, C₁₆H₂₁O₄requires

277.1440.

(1S,2R,4S)-4-Benzoyloxy-1-hydroxy-2-methyl-1-phenylpentan-3-one

(4b):

LRMS (+FAB): m/z = 277 ([M+H]⁺, 18), 259 (20), 154 (100), 136

(65).

R (50% Et₂O in hexane) 0.35; mp 133–135°C; [α] –19.0 (c = 0.8,

f

D

CHCl₃).

IR (CHCl₃): ν = 3396 (br), 1720 (s), 1495 cm^–1(w).

¹H NMR (400 MHz): δ = 1.06 [d, 3 H, J = 7.2 Hz, CH(CH₃)CHOH],

1.49 [d, 3 H, J = 7.1 Hz, CH(CH₃)OBz], 2.78 (br, s, 1 H, OH), 3.14

[dq, 1 H, J = 8.4, 7.2 Hz, CH(CH₃)CHOH], 4.81 [d, 1 H, J = 8.4 Hz,

CH(OH)Ph], 5.40 [q, 1 H, J = 7.1 Hz, CH(CH₃)OBz], 7.35–7.27 (m,

5 H, ArH), 7.43 (dd, 2 H, J = 7.4, 7.3 Hz, ArH), 7.58 (tt, 1 H, J = 7.4,

1.3 Hz, ArH), 8.07 (dd, 2 H, J = 7.3, 1.3 Hz, ArH).

(2S,4R,5R,6S)-2-Benzoyloxy-7-benzyloxy-5-hydroxy-4,6-dimeth-

ylheptan-3-one (12):

General procedure A was followed with ketone (S)-2 (97.3 mg,

0.472 mmol), c-Hex₂BCl (153 µL, 0.706 mmol), Me₂NEt (92 µL,

0.848 mmol) and aldehyde (S)-11 (54.0 mg, 0.272 mmol). Standard

workup and column chromatography (50% Et₂O in hexane) afforded

the aldol product as a colourless oil (83.5 mg, 80%); R (50% Et₂O in

f

¹³C NMR (100.6 MHz): δ = 14.9, 15.3, 49.8, 75.0, 76.5, 126.6, 128.1,

128.4, 128.5, 129.6, 129.8, 133.3, 142.1, 165.9, 211.3.

HRMS (+FAB): m/z [M+H]⁺found 313.1443, C₁₉H₂₁O₄requires

313.1440.

hexane) 0.34; [α] +11.5 (c = 3.8, CHCl₃).

D

IR (film): ν =3505 (br), 1716 (s), 1602 cm^–1(w).

¹H NMR (400 MHz): δ = 0.96 [d, 3 H, J = 7.1 Hz, CH(CH₃)CH₂OBn],

1.12 [d, 3 H, J = 7.1 Hz, CH(CH₃)O], 1.55 [d, 3 H, J = 7.0 Hz,

CH(CH₃)OBz], 1.89 [m, 1 H, CH(CH₃)CH₂OBn], 2.82 (d, 1 H, J =

3.3 Hz, OH), 3.00 [dq, 1 H, J = 9.2, 7.1 Hz, CH(CH₃)CO], 3.52 (dd,

1 H, J = 9.0, 5.4 Hz, CH_AH_BOBn), 3.55 (dd, 1 H, J = 9.0, 4.3 Hz,

CH_AH_BOBn), 4.08 (ddd, 1 H, J = 9.2, 4.9, 3.3 Hz, CHOH), 4.45 (d, 1

H, J = 12.0 Hz, OCH_AH_BPh), 4.50 (d, 1 H, J = 12.0 Hz, OCH_AH_BPh),

5.43 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz], 7.36–7.26 (m, 5H, ArH),

7.43 (dd, 2 H, J = 8.3, 7.5 Hz, ArH), 7.59 (tt, 1 H, J = 7.5, 1.3 Hz,

ArH), 8.08 (dd, 2 H, J = 8.3, 1.3 Hz, ArH).

LRMS (+FAB): m/z = 313 ([M+H]⁺, 75), 289 (52), 177 (100), 154

(92), 136 (85).

(2S,4R,5R)-2-Benzoyloxy-5-hydroxy-4-methylheptan-3-one (4c):

R (50% Et₂O in hexane) 0.28; mp 64–65°C; [α] +41.6 (c = 1.0,

f

D

CHCl₃).

IR (CHCl₃): ν = 3412 (br), 1722 (s), 1602, 1584 cm^–1(w).

¹H NMR (400 MHz): δ = 0.96 (t, 3 H, J = 7.4 Hz, CH₂CH₃), 1.24 [d,

3 H, J = 7.2 Hz, CH(CH₃)CHOH], 1.34–1.45 (m, 1 H, CH_ACH_BCH₃),

1.55 [d, 3 H, J = 7.1 Hz, CH(CH₃)OBz], 1.63–1.57 (m, 1 H,

CH_AH_BCH₃), 2.50 (br, s, 1 H, OH), 2.87 [qn, 1 H, J = 7.2 Hz,

CH(CH₃)CHOH], 3.68 (ddd, 1 H, J = 10.1, 7.2, 3.2 Hz, CHOH), 5.42

[q, 1 H, J = 7.1 Hz, CH(CH₃)OBz], 7.44 (dd, 2 H, J = 8.0, 7.5 Hz,

ArH) 7.57 (tt, 1 H, J = 7.5, 1.0 Hz, ArH), 8.06 (dd, 2 H, J = 8.0, 1.0

Hz, ArH).

13

C NMR (100.6 MHz): δ = 9.6, 13.9, 15.6, 35.6, 45.7, 73.5, 75.0,

75.1(2), 75.1(4), 127.6, 127.7, 128.4, 128.5, 129.7, 129.8, 133.2,

138.0, 165.9, 211.2.

HRMS (+FAB): m/z [M+H]⁺found 385.2028, C₂₃H₂₉O₅requires

385.2015.

LRMS (+FAB): m/z = 407 ([M+Na]⁺, 40), 385 ([M+H]⁺, 100).

¹³C NMR (100.6 MHz): δ = 14.5, 15.9, 27.3, 47.8, 74.7, 128.5, 129.5,

129.8, 133.3, 165.9, 211.9.

(2S,4R,5R,6R)-2-Benzoyloxy-7-benzyloxy-5-hydroxy-4,6-dimeth-

ylheptan-3-one (13):

General procedure A was followed with ketone (S)-2 (111 mg,

0.539 mmol), c-Hex₂BCl (175 µL, 0.808 mmol), Me₂NEt (105 µL,

HRMS (+FAB): m/z [M+H]⁺found 265.1451, C₁₅H₂₁O₄requires

265.1440.

SYNTHESIS

Papers

646

0.970 mmol) and aldehyde (R)-11 (43.0 mg, 0.217 mmol). Standard

workup and column chromatography (50% Et₂O in hexane) afforded

TBS Protection of Aldol Products; Synthesis of 18; General Pro-

cedure B:

the aldol product as a colourless oil (51.0 mg, 61%); R (50% Et₂O in

To a cooled (–78°C) solution of the aldol product 4 (0.5 mmol) in

CH₂Cl₂(3 mL) was added 2,6-lutidine (214 mg, 2 mmol) followed by

TBSOTf (397 mg, 1.5 mmol). The reaction mixture was quenched

with satd aq NaHCO₃solution (10 mL) after 1 h or until TLC analysis

showed consumption of the starting material. It was then allowed to

warm to r.t., partitioned between H₂O (10 mL) and CH₂Cl₂(3 × 25

mL) and the combined organic extracts were dried (MgSO₄), concen-

trated in vacuo and purified by column chromatography.

f

hexane) 0.34; [α] +8.0 (c = 2.0, CHCl₃).

D

IR (film): ν = 3504 (br), 1718 (s), 1602 cm^–1(w).

1

H

NMR (400 MHz): δ = 1.07 [d, 3 H, J = 7.1 Hz,

CH(CH₃)CH OBn], 1.21 [d, 3 H, J = 7.1 Hz, CH(CH₃)CO], 1.52 [d,

2

3 H, J = 7.0 Hz, CH(CH₃)OBz], 1.96 [m, 1 H, CH(CH₃CH₂OBn],

3.07 (d, 1 H, J = 7.7 Hz, OH), 3.13 [qn, 1 H, J = 7.1 Hz, CH(CH₃)CO],

3.55 (m, 2 H, CH₂OBn), 3.69 (ddd, 1 H, J = 7.7, 7.1, 4.4 Hz, CHOH),

4.46 (s, 2 H, OCH₂Ph), 5.43 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz],

7.27–7.34 (m, 5H, ArH), 7.44 (d, 2 H, J = 7.3 Hz, ArH), 7.58 (t, 1 H,

J = 7.3 Hz, ArH), 8.08 (d, 2 H, J = 7.3 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 14.4, 15.6, 35.1, 46.2, 72.0, 73.4, 75.0,

77.0, 127.6, 127.7, 128.4, 128.5, 129.6, 129.8, 133.3, 138.0, 165.8,

211.5.

(2S,4R,5R)-2-Benzoyloxy-5-tert-butyldimethylsilyloxy-4,6-dimethyl-

heptan-3-one (18, R = i-Pr):

R_f(20% Et₂O in hexane) 0.52; [α] +1.8 (c = 1.0, CHCl₃).

D

IR (film): ν = 1724 (s), 1603, 1585 cm^–1(w).

¹H NMR (250 MHz): δ = –0.07 (s, 3 H, SiCH₃), 0.03 (s, 3 H, SiCH₃),

0.87–0.84 [m, 12 H, CH(CH₃)CH₃and SiC(CH₃)₃], 0.94 [d, 3 H, J =

6.8 Hz, CH(CH₃)CH₃], 1.10 [d, 3 H, J = 7.1 Hz, CH(CH₃)CHOTBS],

1.51 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz], 1.78 [septet, d, 1 H, J = 6.8,

2.3 Hz, CH(CH₃)₂], 3.06 [dq, 1 H, J = 8.6, 7.1 Hz, CH(CH₃)CHOT-

BS], 3.88 (dd, 1 H, J = 8.6, 2.3 Hz, CHOTBS), 5.46 [q, 1 H, J = 7.0

Hz, CH(CH₃)OBz], 7.45 (dd, 2 H, J = 8.1, 7.3 Hz, ArH), 7.56 (tt, 1 H,

J = 7.3, 1.0 Hz, ArH), 8.07 (dd, 2 H, J = 8.1, 1.0 Hz, ArH).

¹³C NMR (62.9 MHz): δ = –4.5, –3.5, 14.4, 15.7, 16.1, 18.6, 19.8,

26.4, 31.2, 46.6, 75.1, 77.6, 128.6, 129.8, 129.9, 133.4, 165.8,

209.2.

HRMS (CI, NH₃): m/z [M+H]⁺found 385.2023, C₂₃H₂₉O₅requires

385.2015.

LRMS (CI, NH₃): m/z = 385 ([M+H]⁺, 18), 207 (100), 196 (98), 108

(40).

(2R,4S,5S)-2-Benzoyloxy-4-ethyl-5-hydroxy-6-methylheptan-3-

one (14):

General procedure A was followed with c-Hex₂BCl (128 µL, 0.590

mmol), Me₂NEt (77 µL, 0.708 mmol), ketone (R)-9 (86.5 mg, 0.393

mmol) and i-PrCHO (143 µL, 1.57 mmol). Standard workup and col-

umn chromatography (40% Et₂O in hexane) gave 14 as a white crys-

HRMS (CI, NH₃): m/z [M+H]⁺found 393.2461, C₂₂H₃₇O₄Si requires

393.2461.

talline solid (109.6 mg, 95%): mp 86–88°C; R (40% Et₂O in hexane)

f

LRMS (CI, NH₃): m/z = 393 ([M+H]⁺, 55), 261 (20), 187 (60), 132

(100).

0.25; [α]_D–39 (c = 1.3, CHCl₃).

IR (CHCl₃): ν = 3555 (br), 1725 (s), 1698 (s), 1601, 1585 cm^–1(w).

H NMR (250 MHz): δ = 0.90 [d, 3 H, J = 6.7 Hz, CH(CH)₃CH₃],

1

0.92 [d, 3 H, J = 6.8 Hz, CH(CH₃)CH₃], 0.98 (t, 3 H, J = 7.4 Hz,

CH₂CH₃), 1.56 [d, 3 H, J = 7.1 Hz, CH(CH₃)OBz], 1.75–1.74 [m, 3

H, CH(CH₃)₂and CH₂CH₃], 2.37 (d, 1 H, J = 7.5 Hz, OH), 2.94 [q, 1

H, J = 6.5 Hz, CHCH₂(CH₃)CHOH], 3.55 (ddd, 1 H, J = 7.5, 6.5, 5.2

Hz, CHOH), 5.49 [q, 1 H, J = 7.1 Hz, CH(CH₃)OBz], 7.47 (dd, 2 H,

J = 8.0, 7.6 Hz, ArH), 7.59 (tt, 1 H, J = 7.6, 1.3 Hz, ArH), 8.09 (dd, 2

H, J = 8.0, 1.3 Hz, ArH).

(1S,2R,4S)-4-Benzoyloxy-1-tert-butyldimethylsilyloxy-2-methyl-1-

phenylpentan-3-one (18, R = Ph):

R (20% Et₂O in hexane) 0.46; [α] +43.6 (c = 2.8, CHCl₃).

f

D

IR (film): ν = 1720 (s), 1602, 1558, 1507 cm^–1(w).

¹H NMR (250 MHz): δ = –0.30 (s, 3 H, SiCH₃), –0.07 (s, 3 H, SiCH₃),

0.79 [s, 9 H, SiC(CH₃)₃], 0.83 [d, 3 H, J = 7.1 Hz, CH(CH₃)CHOT-

BS], 1.60 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz], 3.10 [dq, 1 H, J = 9.6,

7.1 Hz, CH(CH₃)CHOTBS], 4.78 [d, 1 H, J = 9.6 Hz, CH(OTBS)Ph],

5.48 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz], 7.27–7.31 (m, 5 H, ArH),

7.46 (dd, 2 H, J = 8.6, 7.4 Hz, ArH), 7.58 (tt, 1 H, J = 7.4, 1.3 Hz,

ArH), 8.09 (dd, 2 H, J = 8.6, 1.3 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 11.7, 16.0, 16.2, 20.0, 22.4, 30.7, 51.3,

75.4, 76.6, 128.5, 129.6, 129.8, 133.4, 165.8, 212.1.

HRMS (+FAB): m/z [M+H]⁺found 293.1734, C₁₇H₂₅O₄requires

293.1753.

LRMS (+FAB): m/z = 293 ([M+H]⁺, 96), 153 (100), 136 (52).

Analysis: found C, 70.07; H, 8.42; C₁₇H₂₄O₄requires C, 69.84; H,

8.27.

¹³C NMR (62.9 MHz): δ = –5.1, –4.8, 14.6, 15.2, 18.0, 25.7, 51.2,

75.3, 77.6, 127.2, 127.8, 128.2, 128.4, 129.7, 129.8, 133.2, 142.6,

165.8, 209.4.

HRMS (CI, NH₃): m/z [M+H]⁺found 427.2305, C₂₅H₃₅O₄Si requires

427.2305.

(2S,4R,5R)-2-Benzoyloxy-4-benzyloxy-5-hydroxy-6-methylhep-

tan-3-one (17):

LRMS (CI, NH₃): m/z = 427 ([M+H]⁺, 18), 211 (40), 177 (100).

General procedure A was followed with c-Hex₂BCl (70 µL, 0.325

mmol), Me₂NEt (44 µL, 0.406 mmol), ketone 15 (48.4 mg, 0.162

mmol) and i-PrCHO (59 µL, 0.650 mmol). Standard workup and col-

umn chromatography (50% Et₂O in hexane) afforded 17 as an oil

(46.4 mg, 77%); R (50% Et₂O in hexane) 0.38; [α] +60.0 (c = 2.2,

(2S,4R,5R,6E)-2-Benzoyloxy-5-tert-butyldimethylsilyloxy-4-methyl-

oct-6-en-3-one (18, R = (E)-CH=CHMe):

R (20% Et₂O in hexane) 0.55; [α] –1.4 (c = 1.4, CHCl₃).

f

D

f

D

IR (film): ν = 1722 (s), 1602 cm^–1(w).

CHCl₃).

¹H NMR (250 MHz): δ = 0.00 (s, 3 H, SiCH₃), , 0.09 (s, 3 H, SiCH₃),

0.81 [s, 9 H, SiC(CH₃)₃], 1.02 [d, 3 H, J = 7.1 Hz, CH(CH₃)CHOT-

BS], 1.52 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz], 1.68 (dd, 3 H, J = 6.5,

1.5 Hz, =CHCH₃), 2.87 [dq, 1 H, J = 9.2, 7.1 Hz, CH(CH₃)CHOTBS],

4.23 (dd, 1 H, J = 9.2, 8.6 Hz, CHOTBS), 5.28 (ddq ,1 H, J = 15.3,

8.6, 1.5 Hz, CH=CHCH₃), 5.42 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz],

5.60 (dq, 1 H, J = 15.3, 6.5 Hz, =CHCH₃), , 7.45 (dd, 2 H, J = 7.3, 7.1

Hz, ArH), 7.58 (tt, 1 H, J = 7.1, 1.2 Hz, ArH), 8.08 (dd, 2 H, J = 7.3,

1.2 Hz, ArH).

IR (film): ν = 3490 (br), 1719 (s), 1601, 1584, 1496 cm^–1(w).

¹H NMR (400 MHz): δ = 0.86 [d, 3 H, J = 6.8 Hz, CH(CH₃)CH₃],

0.98 [d, 3 H, J = 6.9 Hz, CH(CH₃)CH₃], 1.58 [d, 3 H, J = 6.9 Hz,

CH(CH₃)OBz], 1.95 [m, 1 H, CH(CH₃)₂], 2.87 (d, 1 H, J = 6.7 Hz,

OH), 3.80 (m, 1 H, CHOH), 4.09 [d, 1 H, J = 6.9 Hz,

CH(OBn)CHOH], 4.53 ( d, 1 H,J = 11.5 Hz, OCH_AH_BPh), 4.62 (d, 1

H, J = 11.5 Hz, OCH_AH_BPh), 5.66 [q, 1 H, J = 6.9 Hz, CH(CH₃)OBz],

7.35–7.29 (m, 5H, ArH), 7.45 (dd, 2 H, J = 8.1, 7.0 Hz, ArH), 7.57 (tt,

1 H, J = 7.0, 1.1 Hz, ArH), 8.05 (dd, 2 H, J = 8.1, 1.1 Hz, ArH).

¹³C NMR (62.9 MHz): δ = –4.6, –4.0, 14.4, 15.3, 17.7, 18.2, 26.0,

49.1, 75.7, 76.6, 128.5, 128.6, 129.9, 130.0, 132.6, 133.3, 165.9,

209.6.

13

C NMR (100.6 MHz): δ = 16.3, 16.9, 19.9, 29.4, 72.8, 73.9, 76.2,

84.4, 128.2, 128.5, 128.6, 128.7, 129.3, 130.0, 133.6, 136.9, 166.6,

207.9.

HRMS (CI, NH₃): m/z [M+H]⁺found 391.2305, C₂₂H₃₅O₄Si requires

391.2305.

HRMS (CI, NH₃): m/z [M+H]⁺found 371.1858, C₂₂H₂₇O₅requires

371.1858.

LRMS (CI, NH₃): m/z = 391 ([M+H]⁺, 10), 259 (100), 177 (20), 137

(30).

LRMS (CI, NH₃): m/z = 371 ([M+H]⁺, 24), 290 (28), 212 (26), 196

(64), 108 (75), 105 (40), 52 (100).

SYNTHESIS

April 1998

647

(2S,4R,5R,6S)-2-Benzoyloxy-7-benzyloxy-5-tert-butyldimethylsilyl-

oxy-4,6-dimethylheptan-3-one (18, R = (S)-CH(Me)CH₂OBn):

R_f(30% Et₂O in hexane) 0.46; [α]_D–6.4 (c = 1.6, CHCl₃).

IR (film): ν = 1721 (s,), 1602, 1585, 1548, 1512, 1494 cm^–1(w).

¹H NMR (400 MHz): δ = –0.09 (s, 3 H, SiCH₃), 0.01 (s, 3 H, SiCH₃),

0.82 [s, 9 H, SiC(CH₃)₃], 0.89 [d, 3 H, J = 7.1 Hz, CH(CH₃)CH₂OBn],

1.11 [d, 3 H, J = 7.2 Hz, CH(CH₃)CO], 1.50 [d, 3 H, J = 7.0 Hz,

CH(CH₃)OBz], 1.95 [m, 1 H, CH(CH₃)CH₂OBn], 3.10 [dq, 1 H, J =

8.5, 7.2 Hz, CH(CH₃)CO], 3.27 (dd, 1 H, J = 8.8, 6.7 Hz, CH_AH_B

OBn), 3.41 (dd, 1 H, J = 8.8, 7.4 Hz, CH_AH_BOBn), 4.22 (dd, 1 H, J =

8.5, 1.3 Hz, CHOTBS), 4.42 (d, 1 H, J = 12.0 Hz, OCH_AH_BPh), 4.50

(d, 1 H, J = 12.0 Hz, OCH_AH_BPh), 5.47 [q, 1 H, J = 7.0 Hz,

CH(CH₃)OBz], 7.26–7.34 (m, 5H, ArH), 7.45 (t, 2 H, J = 7.4 Hz,

ArH), 7.58 (t, 1 H, J = 7.4 Hz, ArH), 8.06 (d, 2 H, J = 7.4 Hz, ArH).

¹³C NMR (100.6 MHz): δ = –5.0, –3.6, 10.5, 14.0, 15.6, 18.5, 26.2,

36.1, 46.9, 65.9, 72.9, 73.0, 127.4, 127.5, 127.6, 128.3, 128.5, 129.8,

133.3, 165.7, 209.0.

(1S,2S,3R,4S)-1-tert-Butyldimethylsilyloxy-2-methyl-1-phenylpen-

tan-3,4-diol (19, R = Ph):

R_f(60% Et₂O in hexane) 0.25; [α]_D–77.7 (c = 1.6, CHCl₃).

IR (film): ν = 3417 (br), 1603, 1492 cm^–1(w).

¹H NMR (400 MHz): δ = –0.30 (s, 3 H, SiCH₃), 0.02 (s, 3 H, SiCH₃),

0.61 [d, 3 H, J = 6.9 Hz, CH(CH₃)CHOTBS], 0.87 [s, 9H,

SiC(CH₃)₃], 1.15 [d, 3 H, J = 6.3 Hz, CH(CH₃)OH], 1.84 [br sextet, 1

H, J = 7.8 Hz, CH(CH₃)CHOTBS], 2.51 [d, 1 H, J = 8.0 Hz,

CH(CH₃)OH], 3.61 [ddd,

1 H, J = 7.8, 3.5, 1.6 Hz

CH(OH)CH(CH₃)OH], 3.77 [m, 1 H, CH(CH₃)OH], 4.01 (d, 1 H, J =

1.6 Hz, CHOH), 4.62 [d, 1 H, J = 7.8 Hz, CH(OTBS)Ph], 7.32–7.26

(m, 5 H, ArH).

¹³C NMR (100.6 MHz): δ = –5.1, –4.5, 12.0, 16.1, 18.0, 25.8, 43.7,

68.3, 77.5, 80.8, 127.4, 128.1, 142.8.

HRMS (+FAB): m/z [M+H]⁺found 325.2230, C₁₈H₃₃O₃Si requires

325.2199.

LRMS (+FAB): m/z = 347 ([M+Na]⁺55), 325 ([M+H]⁺, 84), 249

(40), 221 (100), 193 (85).

HRMS (+FAB): m/z [M+H]⁺found 499.2876, C₂₉H₄₃O₅Si requires

499.2880.

LRMS (+FAB): m/z = 499 ([M+H]⁺, 24), 441 (51), 349 (25), 293

(50), 259 (75), 179 (100).

(2S,3R,4S,5S,6E)-5-tert-Butyldimethylsilyloxy-4-methyloct-6-en-2,3-

diol (19, R = (E)-CH=CHMe):

R_f(30% Et₂O in CH₂Cl₂) 0.33; [α]_D–18.0 (c = 1.0, CHCl₃).

(2S,4R,5R,6R)-2-Benzoyloxy-7-benzyloxy-5-tert-butyldimethylsilyl-

oxy-4,6-dimethylheptan-3-one (18, R = (R)-CH(Me)CH₂OBn):

R_f(30% Et₂O in hexane) 0.46; [α] _D–5.9 (c = 1.4, CHCl₃).

IR (film): ν = 1721 (s), 1602, 1584, 1495 cm^–1(w).

IR (film): ν = 3380 (s br), 1670 cm–¹(w).

¹H NMR (250 MHz): δ = 0.08 (s, 3 H, SiCH₃), 0.04 (s, 3 H, SiCH₃),

0.75 [d, 3 H, J = 6.9 Hz, CH(CH₃)CHOTBS], 0.89 [s, 9H, SiC(CH₃)₃],

1.15 [d, 3 H, J = 6.3 Hz, CH(CH₃)OH], 1.58 [m, 1 H,

CH(CH₃)CHOTBS], 1.70 (dd, 3 H, J = 6.3, 1.3 Hz, =CHCH₃), 2.58

[d, 1 H, J = 8.1 Hz, CH(CH₃)OH], 3.60 [ddd, 1 H, J = 8.3, 3.5, 2.1 Hz,

CH(OH)CH(CH₃)OH], 3.80 [obscured, 1 H, CH(CH₃)OH], 3.80 (d, 1

H, J = 2.1 Hz, CHOH), 4.06 (t, 1 H, J = 7.8 Hz, CHOTBS), 5.38 (ddq,

1 H, J = 15.4, 7.8, 1.3 Hz, CH=CHCH₃), 5.51 (dq, 1 H, J = 15.4,

6.3 Hz, =CHCH₃).

¹H NMR (400 MHz): δ = –0.07 (s, 3 H, SiCH₃), 0.05 (s, 3 H, SiCH₃)

0.84 [s, 9 H, SiC(CH₃)₃], 0.98 [d, 3 H, J = 7.1 Hz, CH(CH₃)CH₂OBn],

1.11 [d, 3 H, J = 7.1 Hz, CH(CH₃)CO], 1.49 [d, 3 H, J = 7.0 Hz,

CH(CH₃)OBz], 2.08 [m, 1 H, CH(CH₃)CH₂OBn], 3.21 [dq, 1 H, J =

8.7, 7.1 Hz, CH(CH₃)CO], 3.25 (dd, 1 H, J = 9.3, 6.8 Hz, CH_A-

H_BOBn), 3.58 (dd, 1 H, J = 9.3, 6.4 Hz, CH_AH_BOBn), 4.04 (dd, 1 H, J

= 8.7, 2.2 Hz, CHOTBS), 4.44 (s, 2 H, OCH₂Ph), 5.44 [q, 1 H, J = 7.0

Hz, CH(CH₃)OBz], 7.26–7.32 (m, 5H, ArH), 7.43 (d, 2 H, J = 7.4 Hz,

ArH), 7.55 (t, 1 H, J = 7.4 Hz, ArH), 8.05 (d, 2 H, J = 7.4 Hz, ArH).

¹³C NMR (100.6 MHz): δ = –4.9, –3.9, 14.2, 14.9, 15.5, 18.3, 26.1,

37.1, 46.3, 71.7, 72.9, 74.9, 75.9, 127.4, 128.2, 128.3, 128.4, 129.7,

129.8, 133.2, 138.5, 165.7, 209.0.

HRMS (CI, NH₃): m/z [M+H]⁺found 289.2199, C₁₅H₃₃O₃Si requires

289.2199.

LRMS (CI, NH₃): m/z = 289 ([M+H]⁺6), 174 (100), 157 (20), 139

(40).

(2S,3R,4R,5R,6S)-7-Benzyloxy-5-tert-butyldimethylsilyloxy-4,6-di-

methylheptan-2,3-diol (19, R = (S)-CHMeCH OBn):

HRMS (CI, NH₃): m/z [M+H]⁺found 499.2880, C₂₉H₄₃O₅Si requires

499.2880.

2

R_f(30% Et₂O in CH₂Cl₂) 0.38; [α]_D+8.9 (c = 1.4, CHCl₃).

LRMS (CI, NH₃): m/z = 516 ([M+NH₄]⁺, 100), 499 ([M+H]⁺44), 391

(38), 367 (35), 177 (40).

IR (film): ν = 3440 (br), 1558, 1540, 1496 cm^–1(w).

¹H NMR (400 MHz): δ = –0.01 (s, 3 H, SiCH₃), 0.05 (s, 3 H, SiCH₃),

0.80 (d, 3 H, J = 7.0 Hz, CHCH₃), 0.88 (d, 3 H, J = 7.0 Hz, CHCH₃),

0.90 [s, 9H, SiC(CH₃)₃], 1.11 [d, 3 H, J = 6.4 Hz, CH(CH₃)OH],

1.65–1.69 [m, 1 H, CH(CH₃)CH₂OBn], 2.00–2.03 [m, 1 H,

CH(CH₃)CHOH], 2.51 (br, s, 1 H, OH), 3.28–3.31 (m, 1 H, CHOH),

3.54–3.63 (m, 2 H, CH₂OBn), 3.79 (m, 1 H, CHOH), 4.00 (dd, 1 H, J

= 4.5, 2.6 Hz, CHOTBS), 4.48 (d, 1 H, J = 12.0 Hz, OCH_AH_BPh),

4.50 (d, 1 H, J = 12.0 Hz, OCH_AH_BPh), 7.28–7.34 (m, 5 H, ArH).

¹³C NMR (100.6 MHz): δ = –4.8, –4.3, 11.4, 12.5, 15.7, 18.1, 25.9,

35.3, 41.6, 67.7, 73.2, 73.5, 74.2, 75.8, 127.7, 127.8, 128.4, 137.7.

HRMS (+FAB): m/z [M+H]⁺found 397.2784, C₂₂H₄₁O₄Si requires

397.2774.

LiBH₄Reduction of 18; Synthesis of Diols 19; General Procedure C:

To a cooled (–78°C) solution of the protected aldol product 18

(0.5 mmol) in THF (6 mL) was added a 2 M THF solution of LiBH₄

(5.0 mL, 10.0 mmol). The reaction mixture was warmed slowly to r.t.

and stirring was continued for 24 h, before cooling to 0°C and careful

quenching with H₂O. The mixture was partitioned between H₂O

(15 mL) and Et₂O (4 × 25 mL) and the combined organic extracts

washed with brine (30 mL), dried (MgSO₄) and concentrated in vac-

uo. Column chromatography gave the required 1,2-diol.

(2S,3R,4S,5R)-5-tert-Butyldimethylsilyloxy-4,6-dimethylheptan-2,3-

diol (19, R = i-Pr):

LRMS (+FAB): m/z = 419 ([M+Na]⁺, 25), 397 ([M+H]⁺, 100), 265

(40), 187 (38), 157 (50).

R_f(50% Et₂O in hexane) 0.22; [α]_D–7.5 (c = 1.6, CHCl₃).

IR (film): ν = 3418 cm^–1(s br).

(2S,3R,4S,5R,6R)-7-Benzyloxy-5-tert-butyldimethylsilyloxy-4,6-di-

methylheptan-2,3-diol (19, R = (R)-CHMeCH₂OBn):

¹H NMR (400 MHz): δ = 0.09 (s, 3 H, SiCH₃), 0.12 (s, 3 H, SiCH₃)

0.83 [d, 3 H, J = 7.0 Hz, CH(CH₃)CH₃], 0.89 [d, 3 H, J = 6.9 Hz,

CH(CH₃)CH₃], 0.92 [d, 3 H, J = 6.7 Hz, CH(CH₃)CHOH], 0.93 [s,

9H, SiC(CH₃)₃], 1.16 [d, 3 H, J = 6.3 Hz, CH(CH₃)OH], 1.70 [m, 1

H, CH(CH₃)₂], 1.84 [m, 1 H, CH(CH₃)CHOH], 2.63 [d, 1 H, J = 7.0

Hz, CH(CH₃)OH], 3.45 (t, 1 H, J = 4.8 Hz, CHOTBS), 3.48 (d, 1 H,

J = 3.0 Hz, CHOH), 3.63 (ddd, 1 H, J = 9.4, 3.0, 1.2 Hz, CHOH), 3.77

[m, 1 H, CH(CH₃)OH].

R_f(30% Et₂O in CH₂Cl₂) 0.38; [α]_D–2.4 (c = 1.7, CHCl₃).

IR (film): ν = 3440 (br), 1558, 1540, 1496 cm^–1(w).

¹H NMR (400 MHz): δ = 0.08 (s, 3 H, SiCH₃), 0.14 (s, 3 H, SiCH₃),

0.82 (d, 3 H, J = 7.0 Hz, CHCH₃), 0.90 [s, 9H, SiC(CH₃)₃], 0.99 (d, 3

H, J = 6.9 Hz, CHCH₃), 1.13 [d, 3 H, J = 6.4 Hz, CH(CH₃)OH],

1.74–1.78 [m, 1 H, CH(CH₃)CH₂OBn], 2.09–2.13 [m, 1 H,

CH(CH₃)CHOH], 2.68 (br s, 1 H, OH), 3.30 (dd, 1 H, J = 9.2, 6.7 Hz,

CH_AH_BOBn), 3.48 (dd, 1 H, J = 9.2, 6.3 Hz, CH_AH_BOBn), 3.51 (br,

s, 1 H, OH), 3.63 (dd, 1 H, J = 9.3, 3.2 Hz, CHOTBS), 3.75–3.78 (m,

2 H, 2 x CHOH), 4.68 (d, 1 H, J = 17.6 Hz, OCH_AH_BPh), 4.70 (d, 1

H, J = 17.6 Hz, OCH_AH_BPh), 7.26–7.40 (m, 5 H, ArH).

¹³C NMR (100.6 MHz): δ = –4.2, –3.9, 15.6, 15.9, 18.2, 18.3, 19.0,

26.0, 33.6, 38.3, 67.9, 72.6, 82.6.

HRMS (CI, NH₃): m/z [M+H]⁺found 291.2355, C₁₅H₃₅O₃Si requires

291.2356.

LRMS (CI, NH₃): m/z = 291 ([M+H]⁺90), 176 (30), 159 (32), 141

(100).

¹³C NMR (100.6 MHz): δ = –4.5, –4.1, 13.9, 14.9, 15.9, 18.2, 26.0,

38.0, 39.3, 67.9, 72.4, 73.1, 76.2, 78.9, 127.0, 127.7, 128.4, 138.5.

SYNTHESIS

Papers

648

HRMS (+FAB): m/z [M+H]⁺found 397.2766, C₂₂H₄₁O₄Si requires

(2R,3R,4R)-5-Benzyloxy-3-tert-butyldimethylsilyloxy-2,4-dimethyl-

pentanal (5e):³⁰

397.2774.

LRMS (+FAB): m/z = 419 ([M+Na]⁺, 23), 397 ([M+H]⁺,100), 265

R_f(50% CH₂Cl₂in hexane) 0.31.

(35), 173 (40).

IR (film): ν = 1724 (s), 1496 cm^–1(w).

¹H NMR (250 MHz): δ = 0.06 [s, 6 H, Si(CH₃)₂], 0.87 [s, 9 H,

SiC(CH₃)₃], 0.92 [d, 3 H, J = 7.1 Hz, CH(CH₃)CH₂OBn], 1.10 [d, 3

H, J = 7.0 Hz, CH(CH₃)CHO], 2.05 [m, 1 H, CH(CH₃)CH₂OBn], 2.54

[qdd, 1 H, J = 7.0, 3.6, 2.5 Hz, CH(CH₃)CHO], 3.35 (dd, 1 H, J = 9.2,

6.1 Hz, CH_AH_BOBn), 3.46 (dd, 1 H, J = 9.2, 6.2 Hz CH_AH_BOBn),

3.98 (dd, 1 H, J = 5.6, 3.6 Hz, CHOTBS), 4.45 (1 H, d, J = 12.1 Hz,

OCH_AH_BPh), 4.47 (1 H, d, J = 12.1 Hz, OCH_AH_BPh), 7.26–7.37 (5

H, m, ArH), 9.77 (1 H, d, J = 2.5 Hz, CHO).

NaIO₄Cleavage; Synthesis of Aldehydes 5a–e, 24 and 26; General

Procedure D:

To a stirred solution of 1,2-diol (0.2 mmol) in MeOH (2 mL) and H₂O

(1 mL) at r.t. was added NaIO₄(257 mg; 1.2 mmol). The reaction

mixture was stirred at r.t. for 30 min or until TLC analysis showed

consumption of starting material. The reaction mixture was diluted

with H₂O (6 mL), extracted with Et₂O (3 × 15 mL) and then the com-

bined organic extracts were dried (MgSO₄), concentrated in vacuo

and purified by column chromatography.

SmI₂Reduction; Synthesis of 6a,b; General Procedure:

To a cooled (0°C) solution of the protected aldol product 18

(0.05 mmol) in THF (0.6 mL) and MeOH (0.3 mL) was added a 0.1 M

solution of SmI₂in THF until the green colour persisted in the reaction

mixture (typically 3–4 equiv of SmI₂were used). Satd aq K₂CO₃solu-

tion (3 mL) was added and the mixture extracted with Et₂O (3 ×

10 mL). The combined organic extracts were dried (MgSO₄), concen-

trated in vacuo and purified by column chromatography.

(2R,3R)-3-tert-Butyldimethylsilyloxy-2,4-dimethylpentanal (5a):²⁸

R_f(10% Et₂O in hexane) 0.61; [α]_D–49.1 (c = 1.4, CH₂Cl₂).

IR ( film): ν = 1725 cm^–1(s).

¹H NMR (400 MHz): δ = 0.03 (s, 3 H, SiCH₃), 0.50 (s, 3 H, SiCH₃),

0.86–0.85 [m, 15 H, CH(CH₃)₂and SiC(CH₃)₃], 1.07 [d, 3 H, J = 7.1

Hz, CH(CH₃)CHO], 1.82 [m, 1 H, CH(CH₃)₂], 2.51 [m, 1 H,

CH(CH₃)CHO], 3.65 (dd, 1 H, J = 5.0, 4.1 Hz, CHOTBS), 9.76 (d, 1

H, J = 3.3 Hz, CHO).

(4R,5R)-5-tert-Butyldimethylsilyloxy-4,6-dimethylheptan-3-one

(6a):³¹

¹³C NMR (100.6 MHz): δ = –4.3,–4.1, 12.0, 18.2, 18.3, 18.7, 25.9,

32.9, 49.9, 79.2, 205.1.

R_f(5% Et₂O in hexane) 0.5; [α]_D+12.3 (c = 0.6, CHCl₃).

IR (film): ν = 1719 cm^–1(s).

¹H NMR (250 MHz): δ = –0.08 (s, 3 H, SiCH₃), 0.03 (s, 3 H, SiCH₃),

0.85 [s, 9 H, SiC(CH₃)₃], 0.88 [d, 3 H, J = 6.9 Hz, CH(CH₃)CH₃], 0.89

[d, 3 H, J = 6.9 Hz, CH(CH₃)CH₃], 0.94 [d, 3 H, J = 7.1 Hz,

CH(CH₃)CO], 1.01 (t, 3 H, J = 7.2 Hz, CH₂CH₃), 1.73 [septet d, 1 H,

J = 6.9, 3.1 Hz, CH(CH₃)₂], 2.46 (dq, 1 H, J = 18.7, 7.2 Hz,

CH_AH_BCH₃), 2.51 (dq, 1 H, J = 18.7, 7.2 Hz, CH_AH_BCH₃), 2.68 [dq,

1 H, J = 7.7, 7.1 Hz, CH(CH₃)CO], 3.77 (dd, 1 H, J = 7.7, 3.1 Hz,

CHOTBS).

(2R,3S)-3-tert-Butyldimethylsilyloxy-2-methyl-3-phenylpropanal

(5b):

R_f(50% Et₂O in hexane) 0.60; [α]_D–60.0 (c = 0.9, CHCl₃).

IR (film): ν = 1726 (s), 1490 cm^–1(w).

¹H NMR (400 MHz): δ = –0.26 (s, 3 H, SiCH₃), 0.00 (s, 3 H, SiCH₃),

0.84 [s, 9 H, SiC(CH₃)₃], 0.87 [d, 3 H, J = 7.1 Hz, CH(CH₃)CHO],

2.68 [qnd, 1 H, J = 7.1, 2.7 Hz, CH(CH₃)CHO], 4.75 [d, 1 H, J =

7.6 Hz, CH(OTBS)Ph], 7.26–7.35 (m, 5 H, ArH), 9.81 (d, 1 H, J = 2.7

Hz, CHO).

¹³C NMR (62.9 MHz): δ = –4.4, –4.2, 7.4, 13.8, 18.4, 19.7, 26.1, 31.2,

36.8, 50.2, 78.3, 214.3.

¹³C NMR (100.6 MHz): δ = –5.2, –4.5, 11.1, 18.1, 25.7, 54.6, 76.8,

126.7, 127.8, 128.3, 142.3, 204.5.

(1S,2R)-1-tert-Butyldimethylsilyloxy-2-methyl-1-phenylpentan-3-one

(6b):

(2R,3R,4E)-3-tert-Butyldimethylsilyloxy-2-methylhex-4-enal (5c):

R_f(10% Et₂O in hexane) 0.59; [α]_D–51.7 (c = 1.5, CHCl₃).

IR (film): ν = 1729 cm^–1(s).

R_f(5% EtOAc in hexane) 0.38; [α]_D+80.4 (c = 2.2, CHCl₃).

IR (film): ν = 1718 (s), 1603, 1515, 1493 cm^–1(w).

¹H NMR (250 MHz): δ = –0.35 ( s, 3 H, SiCH₃), –0.08 (s, 3 H,

SiCH₃), 0.64 [d, 3 H, J = 7.0 Hz, CH(CH₃)CO], 0.76 [s, 9

H,SiC(CH₃)₃], 1.05 (t, 3 H, J = 7.3 Hz, CH₂CH₃), 2.57 (dd, 1 H, J =

18.5, 7.3 Hz, CH_AH_BCH₃), 2.63 (dd, 1 H, J = 18.5, 7.3 Hz,

CH_AH_BCH₃), 2.88 [dq, 1 H, J = 9.5, 7.0 Hz, CH(CH₃)CHOTBS], 4.64

(d, 1 H, J = 9.5 Hz, CHOTBS), 7.21–7.34 (m, 5 H, ArH).

¹³C NMR (62.9 MHz): δ = –5.4, –4.7, 7.3, 13.8, 17.9, 25.6, 37.9, 53.9,

78.4, 127.0, 127.6, 128.1, 142.8, 214.7.

¹H NMR (400 MHz): δ = –0.01 (s, 3 H, SiCH₃), 0.02 (s, 3 H, SiCH₃),

0.84 [s, 9H, SiC(CH₃)₃], 0.97 [d, 3 H, J = 6.9 Hz, CH(CH₃)CHO],

1.69 (m, 3 H, =CHCH₃), 2.42 [dqd, 1 H, J = 7.1, 6.9, 2.5 Hz,

CH(CH₃)CHO], 4.21 (dd, 1 H, J = 7.5, 7.1 Hz, CHOTBS), 5.40 (ddq,

1 H, J = 15.3, 7.5, 1.6 Hz, CH=CHCH₃), 5.61 (dq, 1 H, J = 15.3, 6.6,

Hz, =CHCH₃), 9.72 (d, 1 H, J = 2.5 Hz, CHO).

¹³C NMR (100.6 MHz): δ = −5.0, −3.9, 10.7, 17.5, 18.1, 25.7, 52.7,

75.4, 127.8, 132.0, 205.0.

HRMS (CI, NH₃): m/z [M+H]⁺found 243.1780, C₁₃H₂₇O₂Si⁺re-

quires 243.1780.

(2S,4R,5S,6E)-2-Benzoyloxy-5-hydroxy-4,6-dimethyloct-6-en-3-

one (28):

LRMS (CI, NH₃): m/z = 243 ([M+H]⁺4), 225 (6), 185 (17), 128 (43),

111 (100).

General procedure A was followed with (S)-2 (540 mg, 2.62 mmol),

c-Hex₂BCl (0.852 mL, 3.93 mmol), Me₂NEt (0.510 mL, 4.72 mmol)

and freshly distilled trans-2-methylbut-2-enal (0.758 mL,

7.86 mmol). Standard workup followed by recrystallisation (Et₂O in

hexane) afforded 28 as a crystalline white solid (659 mg, 86%); mp

92–94°C; [α]_D+28.1 (c = 1.8, CHCl₃).

(2R,3R,4S)-5-Benzyloxy-3-tert-butyldimethylsilyloxy-2,4-dimethyl-

pentanal (5d):

R_f(50% CH₂Cl₂in hexane) 0.31.

IR (film): ν = 1725 (s), 1496 cm^–1(w).

IR CHCl₃): ν = 3517 (br), 1718 (s), 1601 cm^–1(w).

¹H NMR (250 MHz): δ = 0.03 (s, 3 H, SiCH₃), 0.04 (s, 3 H, SiCH₃),

0.86 [s, 9H, SiC(CH₃)₃], 0.94 [d, 3 H, J = 7.0 Hz, CH(CH₃)CH₂],

1.07 [d, 3 H, J = 7.1 Hz, CH(CH₃)CHO], 1.97 [m, 1 H,

CH(CH₃)CH₂OBn], 2.56 [qdd, 1 H, J = 7.1, 5.4, 2.5 Hz,

CH(CH₃)COH], 3.28 (dd, 1 H, J = 9.1, 5.7 Hz, CH_AH_BOBn), 3.37

(dd, 1 H, J = 9.1, 7.0 Hz, CH_AH_BOBn), 4.06 (dd, 1 H, J = 5.4, 3.9 Hz,

CHOTBS), 4.44 (s, 2 H, OCH₂Ph), 7.26–7.37 (m, 5 H, ArH), 9.70 (d,

1 H, J = 2.5 Hz, CHO).

¹H NMR (400 MHz): δ = 1.02 (d, 3 H, J = 7.0 Hz, C₁₂-CH₃), 1.56 (d,

3 H, J = 7.0 Hz, H-16),1.58 (d, 3 H, J = 1.0 Hz, C₁₄-CH₃), 1.60 [d, 3

H, J = 6.7 Hz, CH(CH₃)OBz], 2.00 ( d, 1 H, J = 3.2 Hz, C₁₃-OH), 3.03

(dq, 1 H, J = 9.2, 7.0 Hz, H-12), 4.18 ( dd, 1 H, J = 9.2, 3.2 Hz, H-13),

5.43 (q, 1 H, J = 7.0 Hz, H-15), 5.50 [q, 1 H, J = 6.7 Hz,

CH(CH₃)OBz], 7.45 (t, 2 H, J = 7.5 Hz, ArH), 7.55 (t, 1 H, J = 7.5 Hz,

ArH), 8.02 (d, 2 H, J = 7.5 Hz, ArH).

¹³C NMR (100.6 MHz): δ = 10.4, 13.1, 14.5, 15.6, 45.6, 75.1, 80.1,

124.1, 128.4, 129.6, 129.8, 133.3, 135.1, 166.1, 211.2.

HRMS (CI, NH₃): m/z [M+NH₄]⁺found 308.1862, C₁₇H₂₆O₄N re-

quires 308.1862.

Due to the unstable nature of aldehyde 5d full characterisation was

not obtained but, instead, NaBH₄reduction of 5d and removal of the

TBS group with aq HCl afforded the known (2S,3S,4S)-5-benzyloxy-

2,4-dimethylpentan-1,3-diol.²⁹

SYNTHESIS

April 1998

649

LRMS (CI, NH₃): m/z = 308 ([M+NH₄]⁺, 4), 290 (37), 207 (100), 105

(20).

Analysis: found C, 70.12; H, 7.63; C₁₇H₂₂O₄requires C, 70.32; H,

7.64.

Ba(OH)₂•8H₂O (662 mg, 2.10 mmol, heated to 120°C under vacuum

for 2 h prior to use) in THF (5 mL) was stirred at r.t. for 20 min. A

solution of the aldehyde 24 (283 mg, 1.11 mmol) in THF/H₂O (5 mL,

40:1) was added and the pale yellow suspension stirred at r.t. for 16 h.

The reaction mixture was diluted with CH₂Cl₂(150 mL), washed with

satd aq NaHCO₃solution (70 mL) and brine (70 mL). The organic

layer was dried (MgSO₄), concentrated in vacuo and purified by col-

umn chromatography (5% Et₂O in hexane) to give ester 29 (287 mg,

83%); [α]_D+16.2 (c = 2.6, CHCl₃).

(2S,4R,5S,6E)-2-Benzoyloxy-5-tert-butyldimethylsilyloxy-4,6-

dimethyloct-6-en-3-one:

General procedure B was followed with 28 (824 mg, 2.84 mmol), 2,6-

lutidine (1.00 mL, 8.52 mmol) and TBSOTf (1.30 mL, 5.68 mmol).

Standard workup and column chromatography (20% Et₂O in hex-

anes) afforded the title compound as a colourless oil (1.12 g, 98%);

[α]_D–7.1 (c = 1.7, CHCl₃).

IR (film): ν = 1728 (s), 1659 cm^–1(m).

¹H NMR (400 MHz): δ = –0.09 (s, 3 H, SiCH₃) , –0.03 (s, 3 H,

SiCH₃), 0.85–0.87 [m, 12 H, C₁₂-CH₃and SiC(CH₃)₃], 1.52 (s, 3 H,

C₁₄-CH₃), 1.58 (d, 3 H, J = 6.6 Hz, H-16), 2.42 (m, 1 H, H-12), 3.66

(d, 1 H, J = 8.2 Hz, H-13), 3.70 (s, 3 H,OCH₃), 5.34 (q, 1 H, J =

6.6 Hz, H-15), 5.76 (dd, 1 H, J = 15.8, 1.0 Hz, H-10), 7.00 (dd, 1 H,

J = 15.8, 7.8 Hz, H-11).

IR (film): ν = 1722 (s), 1602, 1585 cm^–1(w).

¹H NMR (250 MHz): δ = –0.07 (s, 3 H, SiCH₃), –0.05 (s, 3 H, SiCH₃),

0.80 [s, 9 H, SiC(CH₃)₃], 0.94 (d, 3 H, J = 7.1 Hz C₁₂-CH₃), 1.51–1.55

(m, 6 H, H-16 and C₁₄-CH₃), 1.59 [d, 3 H, J = 7.0 Hz, CH(CH₃)OBz],

2.99 (dq, 1 H, J = 9.7, 7.1 Hz, H-12), 4.20 (d, 1 H, J = 9.7 Hz, H-13),

5.42 [q, 2 H, J = 7.0 Hz, CH(CH₃)OBz and H-15, overlapping sig-

nals], 7.46 (dd, 2 H, J = 7.4, 6.7 Hz, ArH), 7.59 (tt, 1 H, J = 6.7, 1.3

Hz, ArH), 8.02 (dd, 2 H, J = 7.4, 1.3 Hz, ArH).

¹³C NMR (100.6 MHz): δ = –5.2, –4.7, 10.6, 12.9, 15.8, 18.1, 25.7,

41.1, 51.3, 82.7, 120.2, 122.2, 136.3, 153.3, 167.2.

HRMS (CI, NH₃): m/z [M+H]⁺found 313.2199, C₁₇H₃₃O₃Si⁺re-

quires 313.2199.

¹³C NMR (62.9 MHz): δ = –5.2, –4.9, 10.1, 12.9, 14.5, 15.2, 18.1,

25.8, 47.3, 75.3, 81.3, 123.7, 128.4, 129.7, 129.8, 133.1, 135.3, 165.7,

209.5.

LRMS (CI, NH₃): m/z = 313 ([M+H]⁺, 3), 255 (8), 198 (100), 181

(95).

HRMS (+FAB): m/z [M+H]⁺found 405.2462, C₂₃H₃₇O₄Si requires

405.2461.

(4S,5S,2E,6E)-5-tert-Butyldimethylsilyloxy-4,6-dimethylocta-2,6-

dienol:

LRMS (+FAB): m/z = 405 ([M+H]⁺, 40), 403 ([M–H]⁺, 60), 347 (80),

199 (90), 179 (100).

To a cooled (–78°C) solution of 29 (322 mg, 1.03 mmol) in Et₂O

(15 mL) was added a 1 M solution of DIBAL in hexanes (3.09 mL, 3.09

mmol). The reaction mixture was warmed to –40°C, the stirring contin-

ued for 2 h and then the mixture was quenched with H₂O (25 mL) and

extracted with Et₂O (4 × 25 mL). The combined organic extracts were

dried (MgSO₄), concentrated in vacuo and the resulting oil was purified

by column chromatography (40% Et₂O in hexane) to give the alcohol

as a colourless oil (286 mg, 98%); [α]_D+7.6 (c = 1.5, CHCl₃).

IR (film): ν = 3321 (br s), 1669 cm^–1(w).

(2S,3R,4S,5S,6E)-5-tert-Butyldimethylsilyloxy-4,6-dimethyloct-6-

en-2,3-diol:

General procedure C was followed with the above protected aldol prod-

uct (1.31 g, 3.24 mmol) and a 2 M THF solution of LiBH₄(32.4 mL).

Column chromatography (30% EtOAc in hexane) afforded the diol as a

colourless oil (944 mg, 96%, 90% ds); [α]_D+28.5 (c = 2.6, CHCl₃).

IR (film): ν = 3432 (s br), 1670 cm^–1(w).

¹H NMR (400 MHz): δ = –0.08 (s, 3 H, SiCH₃), –0.03 (s, 3 H, SiCH₃),

0.80 (d, 3 H, J = 6.8 Hz, C₁₂-CH₃), 0.84 [s, 9 H, SiC(CH₃)₃], 1.52 (s,

3 H, C₁₄-CH₃), 1.57 (d, 3 H, J = 6.6 Hz, H-16), 2.25 (m, 1 H, H-12),

3.60 (d, 1 H, J = 8.1 Hz, H-13), 4.08 (d, 2 H, J = 5.4 Hz, H-9), 5.31

(q, 1 H, J = 6.6 Hz, H-15), 5.60 (dt, 1 H, J = 15.8, 5.4 Hz, H-10), 5.68

(dd, 1 H, J = 15.8, 7.2 Hz, H-11).

¹H NMR (400 MHz): δ = –0.01 (s, 3 H, SiCH₃), 0.09 ( s, 3 H, SiCH₃),

0.63 (d, 3 H, J = 6.9 Hz, C₁₂-CH₃), 0.88 [s, 9H, SiC(CH₃)₃], 1.15 [d,

3 H, J = 6.4 Hz, CH(CH₃)OH], 1.54 (s, 3 H, C₁₄-CH₃), 1.58 (d, 3 H,

J = 6.6 Hz, H-16), 1.63 (m, 1 H, H-12), 2.60 [d, 1 H, J = 9.7 Hz,

CH(CH₃)OH], 3.64 (dd, 1 H, J = 8.4, 3.2 Hz, H-11), 3.77 [m, 1 H,

CH(CH₃)OH], 3.88 (d, 1 H, J = 9.1 Hz, H-13), 4.44 (br s, 1 H,

C₁₁–OH), 5.38 (q, 1 H, J = 6.6 Hz, H-15).

¹³C NMR (100.6 MHz): δ = –4.79, –4.38, 11.1, 13.1, 17.0, 18.3, 26.1,

41.0, 64.4, 83.5, 121.7, 128.5, 137.29, 137.30.

¹³C NMR (100.6 MHz): δ = –5.2, –4.3, 10.8, 12.8, 13.0, 10.0, 16.1,

25.9, 38.6, 68.6, 78.1, 86.6, 123.8, 136.0.

HRMS (+FAB): m/z [M–H]⁺found 283.2199, C₁₆H₃₁O₂Si⁺requires

283.2093.

HRMS (CI, NH₃): m/z [M+H]⁺found 303.2355, C₁₆H₃₅O₃Si requires

303.2355.

LRMS (+FAB): m/z = 283 ([M–H]⁺, 70), 267 (50), 227 (35), 199

(100), 159 (60).

LRMS (CI, NH₃): m/z = 303 ([M+H]⁺, 14), 287 (42), 273 (20), 188

(33), 171 (100), 153 (42).

(4S,5S,2E,6E)-5-tert-Butyldimethylsilyloxy-4,6-dimethylocta-2,6-

dienal (23):

(2R,3S,4E)-3-tert-Butyldimethylsilyloxy-2,6-dimethylhex-4-enal

(24):³²

To a solution of Dess–Martin periodinane (592 mg, 1.38 mmol) in

CH₂Cl₂(5 mL) at r.t. was added the above alcohol (262 mg,

0.923 mmol) in CH₂Cl₂(10 mL) via cannula. The mixture was stirred

for 1 h before pouring into a 1:1 mixture of satd aq NaHCO₃/Na₂S₂O₃

solution (15 mL). The separated aqueous layer was extracted with

Et₂O (4 × 30 mL) and the combined organic extracts dried (MgSO₄)

and concentrated in vacuo. The crude mixture was purified by column

chromatography (30% Et₂O in hexane) to afford aldehyde 23 as a co-

lourless oil (246 mg, 95%); [α]_D–19.6 (c = 2.5, CHCl₃).

General procedure D was followed with the above diol (360 mg,

1.19 mmol) and NaIO₄(1.53 g, 7.15 mmol). Rapid column chroma-

tography (20% Et₂O in hexane) afforded aldehyde 24 as a colourless

oil (283 mg, 93%); [α]_D+30.6 (c = 1.7, CHCl₃).

IR (film): ν = 1729 (s), 1670 cm^–1(w).

¹H NMR (400 MHz): δ = –0.06 (s, 3 H, SiCH₃), 0.00 (s, 3 H, SiCH₃),

0.82–0.84 [m, 12 H, SiC(CH₃)₃and C₁₂-CH₃], 1.55 (s, 3 H, C₁₄-CH₃),

1.60 (d, 3 H, J = 6.7 Hz, H-16), 2.54 (dqd, 1 H, J = 8.8, 7.2, 2.8 Hz,

H-12), 4.04 (d, 1 H, J = 8.8 Hz, H-13), 5.43 (q, 1 H, J = 6.7 Hz, H-

15), 9.73 (d, 1 H, J = 2.8 Hz, H-11).

IR (film): ν = 1695 (s), 1636 cm^–1(w).

1

H NMR (400 MHz): δ = –0.07 (s, 3 H, SiCH₃), –0.02 (s, 3 H, SiCH ),

3

¹³C NMR (100.6 MHz): δ = –5.2, –4.4, 10.7, 11.1, 13.1, 16.2, 25.9,

50.4, 80.7, 123.3, 135.5, 205.7.

0.85 [s, 9 H, SiC(CH₃)₃], 0.91 (d, 3 H, J = 6.8 Hz, C₁₂-CH₃), 1.54 (s,

3 H, C₁₄-CH₃), 1.58 (d, 3 H, J = 6.7 Hz, H-16), 2.57 (m, 1 H, H-12),

3.73 ( d, 1 H, J = 7.9 Hz, H-13), 5.38 (q, 1 H, J = 6.7 Hz, H-15), 6.09

(ddd, 1 H, J = 15.7, 7.9, 1.1 Hz, H-10), 6.92 (dd, 1 H, J = 15.7, 7.4 Hz,

H-11), 9.48 (d, 1 H, J = 7.9 Hz, H-9).

HRMS (CI, NH₃): m/z [M+H]⁺found 257.1937, C₁₄H₂₉O₂Si requires

257.1937.

LRMS (CI, NH₃): m/z = 257 ([M+H]⁺,12), 199 (66), 142 (100), 125

(100).

¹³C NMR (100.6 MHz): δ = –5.2, –4.6, 10.8, 12.9, 18.1, 25.7, 41.5,

82.6, 122.6, 132.3, 136.1, 162.6, 194.2.

HRMS (+FAB): m/z [M]⁺found 282.2025, C₁₆H₃₀O₂Si requires

282.2015.

Methyl (4S,5S,2E,6E)-5-tert-Butyldimethylsilyloxy-4,6-dimethyl-

octa-2,6-dienoate (29):

A mixture of (MeO)₂P(O)CH₂CO₂Me (0.358 mL, 2.21 mmol) and

LRMS (+FAB): m/z = 282 ([M]⁺, 40), 225 (55), 199 (100).

SYNTHESIS

Papers

650

(2S,4R,5R,8S,9S,6E,10E)-2-Benzoyloxy-9-tert-butyldimethylsilyl-

oxy-5-hydroxy-4,8,10-trimethyldodeca-6,10-dien-3-one (30):

General procedure A was followed with ketone (S)-2 (140 mg,

0.680 mmol), c-Hex₂BCl (221 µL, 1.02 mmol), Me₂NEt (132 µL,

1.22 mmol) and aldehyde 23 (101 mg, 0.358 mmol). Standard workup

and column chromatography (1% Et₂O in CH₂Cl₂) afforded 30 as a

colourless oil (166 mg, 95%); [α]_D+4.2 (c = 0.9, CHCl₃).

IR (film): ν = 3524 (br m), 1720 (s), 1602, 1558 cm^–1(w).

¹H NMR (400 MHz): δ = –0.09 (s, 3 H, SiCH₃), –0.04 (s, 3 H,

SiCH₃), 0.80 (d, 3 H, J = 6.9 Hz, C₁₂-CH₃), 0.83 [s, 9 H, SiC(CH₃)₃],

1.12 (d, 3 H, J = 7.1 Hz, C₈-CH₃), 1.50 (s, 3 H, C₁₄-CH₃), 1.55 [d, 3

H, J = 7.0 Hz, CH(CH₃)OBz], 1.56 (d, 3 H, J = 6.6 Hz, H-16), 1.97

(d, 1 H, J = 3.1 Hz, C₉-OH), 2.27 (m, 1 H, H-12), 2.87 (dq, 1 H, J =

8.4, 7.1 Hz, H-8), 3.61 (d, 1 H, J = 7.7 Hz, H-13), 4.20 (m, 1 H, H-9),

5.31 (q, 1 H, J = 6.6 Hz, H-15), 5.36 (dd, 1 H, J = 15.5, 7.9 Hz, H-10),

5.42 [q, 1 H, J = 7.0 Hz, CH(CH₃)OBz], 5.76 (dd, 1 H, J = 15.5, 7.1

Hz, H-11), 7.43 (t, 2 H, J = 7.4 Hz, ArH), 7.56 (t, 1 H, J = 7.4 Hz,

ArH), 8.02 (d, 2 H, J = 7.4 Hz, ArH).

¹³C NMR (100.6 MHz): δ = –5.1, –4.8, –4.6, –3.6, 11.8, 12.6, 12.9,

16.2, 16.6, 18.2, 18.3, 25.8, 39.8, 41.9, 68.3, 77.4, 80.0, 82.4, 120.9,

130.4, 135.7, 136.8.

HRMS (+FAB): m/z [M–H]⁺found 499.3667, C₂₇H₅₅O₄Si₂requires

499.3639.

LRMS (+FAB): m/z = 523 ([M+Na]⁺, 30), 499 ([M–H]⁺, 55), 369

(95), 199 (100).

(2R,3R,6S,7S,4E,8E)-3,7-Di-tert-butyldimethylsilyloxy-2,6,8-tri-

methyldeca-4,8-dienal (26):

General procedure D was followed with the above diol (80.0 mg,

0.160 mmol) and NaIO₄(1.03 g, 4.80 mmol). Column chromatogra-

phy (20% Et₂O in hexane) afforded 26 as a colourless oil (68 mg,

94%); [α]_D–33.6 (c = 2.2, CHCl₃).

IR (film): ν = 1729 (s), 1668 cm^–1(w).

¹H NMR (400 MHz): δ = –0.07 (s, 3 H, SiCH₃), –0.02 (s, 3 H, SiCH₃),

–0.01 (s, 3 H, SiCH₃), 0.02 (s, 3 H, SiCH₃), 0.85 [s, 9 H, SiC(CH₃)₃],

0.87 [s, 9 H, SiC(CH₃)₃], 0.87 (d, 3 H, J = 6.6 Hz, C₁₂-CH₃), 0.97 (d,

3 H, J = 7.0 Hz, C₈-CH₃), 1.52 (s, 3 H, C₁₄-CH₃), 1.56 (d, 3 H, J = 7.1

Hz, H-16), 2.32 (m, 1 H, H-12), 2.42 (qn d, 1 H, J = 7.0, 2.6 Hz, H-

8), 3.68 (d, 1 H, J = 6.4 Hz, H-13), 4.21 (t, 1 H, J = 7.0 Hz, H-9)

5.31–5.37, (m, 2 H, H-10,15), 5.81 (dd, 1 H, J = 15.7, 6.6 Hz, H-11),

9.72 (d, 1 H, J = 2.6 Hz, H-7).

¹³C NMR (100.6 MHz): δ = –5.1, –4.7, 11.0, 12.8, 14.5, 15.5, 16.7,

18.2, 25.8, 40.6, 48.2, 75.0, 75.5, 83.0, 121.4, 128.4, 129.1, 129.4,

129.8, 133.2, 136.6, 138.3, 165.3, 210.9.

HRMS (+FAB): m/z [M+H]⁺found 489.3006, C₂₈H₄₅O₅Si requires

489.3036.

LRMS (+FAB): m/z = 489 ([M+H]⁺, 20), 487 ([M–H]⁺, 50), 471 (80),

357 (80), 199 (100).

¹³C NMR (100.6 MHz): δ = –5.1, –5.0, –4.6, –3.8, 10.8, 11.8, 12.9,

17.1, 18.0, 18.2, 25.8, 25.9, 40.1, 52.9, 75.7, 82.4, 120.8, 129.6,

135.8, 136.8, 205.0.

(2S,4R,5R,8S,9S,6E,10E)-2-Benzoyloxy-5,9-di-tert-butyldimeth-

ylsilyloxy-4,8,10-trimethyldodeca-6,10-dien-3-one:

HRMS (+FAB): m/z [M–H]⁺found 453.3189, C₂₅H₄₉O₃Si₂requires

453.3220.

General procedure B was followed with 30 (166 mg, 0.340 mmol),

2,6-lutidine (100 µL, 0.848 mmol) and TBSOTf (156 µL, 0.679

mmol). Standard workup and column chromatography (7% EtOAc in

hexane) afforded the silyl ether as a colourless oil (203 mg, 99%);

[α]_D–1.2 (c = 1.7, CHCl₃).

LRMS (+FAB): m/z = 453 ([M–H]⁺, 90), 395 (65), 381 (50), 341

(75), 301 (60), 199 (100).

IR (film): ν = 1723 (s), 1602, 1585 cm^–1(w).

(2'S,3'S,4'R,7'S,8'S,5'E,9'E)-4-Methoxy-6-(4',8'-di-tert-butyldi-

methylsilyloxy-3',7',9'-trimethylundeca-5',9'-dien-2'-ol)-2H-pyr-

an-2-one (31):

¹H NMR (100.6 MHz): δ = –0.07 (s, 3 H, SiCH₃), –0.03 (s, 3 H,

SiCH₃), –0.02 (s, 3 H, SiCH₃), –0.01 (s, 3 H, SiCH₃), 0.81 [s, 9 H,

SiC(CH₃)₃], 0.87–0.90 [m, 12 H, C₁₂-CH₃and SiC(CH₃)₃], 1.01 (d, 3

H, J = 7.1 Hz, C₈-CH₃), 1.49 (s, 3 H, C₁₄-CH₃), 1.53 [d, 3 H, J = 6.9

Hz, CH(CH₃)OBz], 1.57 (d, 3 H, J = 6.7 Hz, H-16), 2.27 (m, 1 H, H-

12), 2.85 (dq, 1 H, J = 8.2, 7.1 Hz H-8), 3.69 (d, 1 H, J = 6.6 Hz, H-

13), 4.23 (t, 1 H, J = 8.2 Hz, H-9), 5.20 (q, 1 H, J = 6.7 Hz, H-15),

5.20 (dd, 1 H, J = 15.5, 8.2 Hz, H-10), 5.41 [q, 1 H, J = 6.9 Hz,

CH(CH₃)OBz], 5.67 (dd, 1 H, J = 15.7, 6.6 Hz, H-11), 7.44 (dd, 2 H,

J = 7.8, 7.4 Hz, ArH), 7.56 (tt, 1 H, J = 7.4, 1.1 Hz, ArH), 8.07 (dd, 2

H, J = 7.8, 1.1 Hz, ArH).

To a cooled (–100°C) solution of 27 (167 mg, 1.19 mmol) in Et₂O

(6 mL), was added a 0.5 M solution of potassium bis(trimethylsi-

lyl)amide (KHMDS) in toluene (2.08 mL, 1.04 mmol) and the stir-

ring was continued at –100°C for 1 h. A cooled (–78°C) solution

of 26 (63.0 mg, 0.139 mmol) in Et₂O (6 mL) was added via cannu-

la, and stirring was continued for a further 2 h. The reaction was

quenched by the addition of MeOH (5 mL) at –100°C and allowed

to warm to r.t., whereupon the mixture was diluted with H₂O (10

mL) and extracted with CH₂Cl₂(3 × 20 mL). The combined organ-

ic extracts were dried (MgSO₄) and concentrated in vacuo. Col-

umn chromatography (40% EtOAc in hexane) yielded the

protected toxin (67.4 mg, 82%) as a 2.5:1 ratio of epimers at C₇.

HPLC separation (40% EtOAc in hexane) gave 31 (39.2 mg, 48%)

and 7-epi-31 (16 mg, 19%).

¹³C NMR (100.6 MHz):δ = –5.0, –4.7, –4.5, –3.9, 11.8, 12.8, 14.5,

15.1, 17.1, 18.0, 18.3, 25.9, 26.0, 40.5, 49.0, 75.4, 76.9, 82.2, 120.8,

128.3, 128.4, 129.8, 130.3, 133.2, 136.3, 136.7, 165.8, 209.5.

HRMS (+FAB): m/z [M–H]⁺found 601.3723, C₃₄H₅₇O₅Si₂requires

601.3744.

LRMS (+FAB): m/z = 601 ([M–H]⁺, 40), 546 (35), 341 (75), 295

(90), 199 (100), 179 (80).

31: [α]_D–46.0 (c = 2.0, CHCl₃).

IR (film): ν = 3432 (br s), 1701 (s), 1648 cm^–1(m).

1

(2S,3R,4S,5R,8S,9S,6E,10E)-5,9-Di-tert-butyldimethylsilyloxy-

4,8,10-trimethyldodeca-6,10-diene-2,3-diol:

H NMR (400 MHz): δ = –0.08 (s, 3 H, SiCH₃)., –0.03 (s, 3 H,

SiCH₃), 0.01 (s, 3 H, SiCH₃), 0.07 (s, 3 H, SiCH₃), 0.80 (d, 3 H, J =

6.9 Hz, C₈-CH₃), 0.85–0.87 [m, 21 H, 2 x SiC(CH₃)₃and C₁₂-CH₃],

1.51 (s, 3 H, C₁₄-CH₃), 1.55 (d, 3 H, J = 6.6 Hz, H-16), 1.64 (m, 1 H,

H-8), 2.33 (m, 1 H, H-12), 2.45 (dd, 1 H, J = 14.8, 9.4 Hz, C₆-H_AH_B),

2.74 (dd, 1 H, J = 14.8, 2.2 Hz, C₆-H_AH_B), 3.66 (d, 1 H, J = 6.6 Hz,

H-13), 3.77 (s, 3 H, OCH₃), 3.96–4.02 (m, 3 H, H-7 and C₇-OH and

H-9), 5.31 (dd, 1 H, J = 15.9, 7.9 Hz, H-10), 5.35 (q, 1 H, J = 6.6 Hz,

H-15), 5.40 (d, 1 H, J = 2.1 Hz, H-2), 5.80 (dd, 1 H, J = 15.9, 5.9 Hz,

H-11), 5.95 (d, 1 H, J = 2.1 Hz, H-4).

General procedure C was followed with the above protected aldol

product (219 mg, 0.364 mmol) and a 2 M THF solution of LiBH₄

(3.64 mL, 7.27 mmol). Column chromatography (30% EtOAc in hex-

ane) afforded the diol as a colourless oil (166 mg, 91%, 90% ds); [α]_D

–24 (c = 1.0, CHCl₃).

IR (film): ν = 3422 (br s), 1669 cm^–1(w).

¹H NMR (400 MHz): δ = –0.07 (s, 3 H, SiCH₃), –0.02 (s, 3 H, SiCH₃),

0.03 (s, 3 H, SiCH₃), 0.08 (s, 3 H, SiCH₃), 0.74 (d, 3 H, J = 6.9 Hz,

C₈-CH₃), 0.87 [s, 9 H, SiC(CH₃)₃], 0.88–0.90 [m, 12 H, C₁₂-CH₃and

SiC(CH₃)₃], 1.15 [d, 3 H, J = 6.3 Hz, CH(CH₃)OH], 1.52 (s, 3 H, C₁₄-

CH₃), 1.56 (d, 3 H, J = 6.7 Hz, H-16), 2.32–2.33 (m, 2 H, H-8,12),

3.60 (dd, 1 H, J= 8.1, 3.6 Hz, H-7), 3.67 (br s, 1 H, OH), 3.68 (d, 1 H,

J = 4.3 Hz, H-13), 3.78 [qd, 1 H, J = 6.3, 3.6 Hz, CH(CH₃)OH], 3.88

(br, s, 1 H, OH), 4.06 (t, 1 H, J = 7.6 Hz, H-9), 5.34–5.35 (m, 2 H, H-

10,15), 5.78 ( dd, 1 H,J = 15.9, 5.9 Hz, H-11).

¹³C NMR (100.6 MHz): δ = –5.1, –4.7, –4.6, –3.5, 11.7, 12.9, 13.5,

16.5, 18.0, 18.2, 25.9, 25.9, 39.2, 39.7, 44.5, 55.7, 72.3, 80.3, 82.5,

87.8, 101.7, 121.0, 130.5, 135.9, 136.8, 136.3, 165.1, 171.3.

HRMS (+FAB): m/z [M–H]⁺found 593.3715, C₃₂H₅₇O₆Si₂requires

593.3694.

LRMS (+FAB): m/z = 593 ([M–H]⁺, 5), 537 (50), 379 (60), 331 (80),

199 (100).

SYNTHESIS

April 1998

651

(3'R,4'R,7'S,8'S,5'E,9'E)-4-Methoxy-6-(4',8'-di-tert-butyldimeth-

ylsilyloxy-3',7',9'-trimethylundeca-5',9'-dien-2'-one)-2H-pyran-

2-one (32):

¹H NMR (400 MHz): δ = 0.84 (d, 3 H, J = 6.8 Hz, C₈-CH₃), 0.85 (d,

3 H, J = 6.9 Hz, C₁₂-CH₃), 1.58 (s, 3 H, C₁₄-CH₃), 1.63 (d, 3 H, J =

6.9 Hz, H-16) 1.71 (m, 1 H, H-8), 2.32 (m, 1 H, H-12), 2.47 (dd, 1 H,

J = 14.8, 9.4 Hz, C₆-H_AH_B), 2.80 (dd, 1 H, J = 14.8, 2.2 Hz, C₆-

H_AH_B), 3.65 (d, 1 H, J = 6.9 Hz, H-13), 3.78 (s, 3 H, CH₃O), 4.07 (m,

1 H, H-7), 4.09 (m, 1 H, H-9), 5.41 (d, 1 H, J = 2.1 Hz, H-2), 5.46 (q,

1 H, J = 7.2 Hz, H-15), 5.57 (m, 1 H, H-10), 5.61 (m, 1 H, H-11), 5.94

(d, 1 H, J = 2.1 Hz, H-4).

To a solution of Dess–Martin periodinane (179 mg, 0.418 mmol) in

CH₂Cl₂(3 mL) at r.t. was added a mixture of alcohols 31 and 7-epi-

31 (124 mg, 0.209 mmol) in CH₂Cl₂(2 mL) via cannula. The reaction

mixture was stirred for 2 h, before pouring into a 1:1 mixture of satd

aq NaHCO₃/Na₂S₂O₃solution (8 mL). The separated aqueous layer

was extracted with CH₂Cl₂(3 × 25 mL) and the combined organic ex-

tracts were dried (MgSO₄) and concentrated in vacuo. Column chro-

matography (40% EtOAc in hexane) afforded ketone 32 as a

colourless oil (112 mg, 91%); [α]_D–54.2 (c = 1.5, CHCl₃).

IR (film): ν = 1729 (s), 1654 cm^–1(m).

¹³C NMR (100.6 MHz): δ = 10.5, 13.1, 13.4, 17.2, 39.4, 40.4, 43.4,

55.8, 72.7, 77.9, 82.3, 87.8, 101.9, 123.3, 132.8, 135.9, 136.5, 163.2,

165.2, 171.4.

HRMS (+FAB): m/z [M+H]⁺found 367.2121, C₂₀H₃₁O₆requires

367.2121.

¹H NMR (400 MHz): δ = –0.08 (s, 3 H, SiCH₃), –0.04 (s, 3 H, SiCH₃),

–0.03 (3s, H, SiCH₃), –0.02 (s, 3 H, SiCH₃), 0.82 [s, 9 H, SiC(CH₃)₃],

0.87 [s, 9 H, SiC(CH₃)₃], 0.87 (d, 3 H, J = 6.7 Hz, C₁₂-CH₃), 0.92 (d,

3 H, J = 7.0 Hz, C₈-CH₃), 1.53 (s, 3 H, C₁₄-CH₃), 1.55 (d, 3 H, J = 6.7

Hz, H-16), 2.30 (sextet, 1 H, J = 6.7 Hz, H-12), 2.71 (dq, 1 H, J = 8.1,

7.0 Hz, H-8), 3.60 (d, 1 H, J = 17.1 Hz, C₆-H_AH_B), 3.63 (d, 1 H, J =

17.1 Hz, C₆-H_AH_B), 3.66 (d, 1 H, J = 6.7 Hz, H-13), 3.78 (s, 3 H,

CH₃O), 4.10 (t, 1 H, J = 8.1 Hz, H-9), 5.21 (ddd, 1 H, J = 15.8, 8.1,

1.2 Hz, H-10), 5.35 (q, 1 H, J = 6.7 Hz, H-15), 5.43 (d, 1 H, J = 2.2

Hz, H-2), 5.80 (dd, 1 H, J = 15.8, 6.7 Hz, H-11), 5.91 (d, 1 H, J = 2.2

Hz, H-4).

LRMS (+FAB): m/z = 367 ([M+H]⁺, 70), 331 (90), 265 (50), 169

(100).

7-epi-ACRL Toxin IIIB:

mp 162–165°C; [α]_D+66.7 (c = 0.3, CHCl₃).

IR (CHCl₃): ν = 3408 (br s), 1698 (s), 1644 cm^–1(m).

¹H NMR (250 MHz): δ = 0.82 (d, 3 H, J = 6.8 Hz, C₁₂-CH₃), 0.97 (d,

3 H, J = 7.1 Hz, C₈-CH₃), 1.60 (s, 3 H, C₁₄-CH₃), 1.62 (d, 3 H, J = 6.8

Hz, H-16), 1.68 (m, 1 H, H-8), 2.34 (m, 1 H, H-12), 2.51 (dd, 1 H, J

= 14.4, 3.1 Hz, C₆-H_AH_B), 2.62 (dd, 1 H, J = 14.4, 9.6 Hz, C₆-H_AH_B),

3.62 (d, 1 H, J = 9.1 Hz, H-13), 3.78 (s, 3 H, CH₃O), 4.10 (m, 1 H, H-

7), 4.41–4.32 (m, 1 H, H-9), 5.41 (d, 1 H, J = 2.2 Hz, H-2), 5.62–5.44

(m, 3 H, H-10,11,15), 5.92 (d, 1 H, J = 2.2 Hz, H-4).

HRMS (+FAB): m/z [MH–H₂O]⁺found 349.2024, C₂₀H₂₉O₅requires

349.2015.

¹³C NMR (100.6 MHz): δ = –5.1, –5.0, –4.6, –3.9, 11.7, 12.9, 13.6,

16.7, 18.0, 18.2, 25.8, 25.9, 39.2, 48.5, 52.6, 55.8, 77.7, 82.3, 88.4,

102.9, 120.9, 129.6, 136.5, 136.7, 158.0, 164.3, 170.8, 206.9.

(3'R,4'R,7'S,8'S,5'E,9'E)-4-Methoxy-6-(4',8'-dihydroxy-3',7',9'-

trimethylundeca-5',9'-dien-2'-one)-2H-pyran-2-one (33):

To a cooled (0°C) solution of 32 (14.1 mg, 0.0238 mmol) in THF

(2 mL) was added HF•pyridine (0.4 mL). The stirring was continued

for 1 h at 0°C, followed by 1 h at r.t. H₂O (5 mL) was added and the

mixture extracted with Et₂O (4 × 8 mL). The combined organic ex-

tracts were washed with satd aq NaHCO₃solution (2 × 5 mL), dried

(Na₂SO₄) and concentrated in vacuo. Column chromatography

(EtOAc) yielded ketone 33 as a crystalline white solid (6.4 mg, 74%);

mp 144–146°C; [α]_D–35.7 (c = 0.3, CHCl₃).

LRMS (+FAB): m/z = 367 ([M+H]⁺, 18), 349 ([MH–H₂O]⁺, 20), 331

(70), 199 (100).

We thank the EPSRC (GR/J63019 and K54052), EC (HCM Network

CHRXCT930141), BP Chemicals and Churchill College (Research

Fellowship to DJW) for their support, Silvia M. Velázquez for provid-

ing some experimental assistance and Prof J. Mulzer for providing

further details of his ACRL toxin IIIB synthesis.

IR (CHCl₃): ν = 3378 (br s), 1716, 1681 (s), 1643 cm^–1(m).

¹H NMR (400 MHz): δ = 0.78 (d, 3 H, J = 7.0 Hz, C₁₂-CH₃), 1.00 (d, 3

H, J = 7.1 Hz, C₈-CH₃), 1.56 (s, 3 H, C₁₄-CH₃), 1.59 (d, 3 H, J = 6.8 Hz,

H-16), 2.29 (dqn, 1 H, J = 8.3, 7.0 Hz, H-12), 2.71 (qn, 1 H, J = 7.1 Hz,

H-8), 3.60 (d, 1 H, J = 7.0 Hz, H-11), 3.65 (d, 1 H, J = 17.2 Hz, C₆-

H_AH_B), 3.69 (d, 1 H, J = 17.2 Hz, C₆-H_AH_B), 3.78 (s, 3 H, CH₃O), 4.10

(dd, 1 H, J = 7.7, 7.1 Hz, H-9), 5.47–5.42 (m, 3 H, H-2,10,15), 5.55 (dd,

1 H, J = 15.3, 8.3 Hz, H-11), 5.95 (d, 1 H, J = 2.3 Hz, H-4).

¹³C NMR (100.6 MHz): δ = 10.4., 13.1, 13.5, 17.3, 40.5, 47.4, 51.5,

55.9, 75.7, 82.2, 88.3, 103.2, 123.4, 131.5, 136.0, 137.7, 158.1, 164.6,

171.0, 207.4.

(1) For recent reviews on asymmetric aldol reactions, see:

Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.

Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.

Heathcock, C. H.; Kim, B. M.; Williams, S. F.; Masamune, S.;

Paterson, I.; Gennari, C. In Comprehensive Organic Synthesis;

Vol 2, Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,

1991.

(2) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,

119, 2586, and references cited therein.

(3) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M.

A. J. Am. Chem. Soc. 1994, 116, 11287.

HRMS (+FAB): m/z [M+H]⁺found 365.1986, C₂₀H₂₉O₆requires

365.1964.

LRMS (+FAB): m/z = 387 ([M+Na]⁺, 47), 365 ([M+H]⁺, 30), 347

(75), 329 (100), 154 (80).

Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.

Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,

30, 7121.

(–)-ACRL Toxin IIIB (7):

(4) Paterson, I.; Wallace, D. J.; Velázquez, S. M. Tetrahedron Lett.

1994, 35, 9083.

(5) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35, 9087.

(6) Wallace, D. J. Ph.D. Dissertation, University of Cambridge,

1995.

To a cooled (–78°C) solution of 33 (6.8 mg, 0.0187 mmol) in THF

(1 mL) and MeOH (0.2 mL) was added a 2.9 M MeOH solution of

Bu₂BOMe (26 µL, 0.0747 mmol), and the stirring was continued for

20 min to allow complex formation. A 2 M THF solution of LiBH₄

(37 µL, 0.0747 mmol) was added and the reaction mixture stirred at

–78°C for 2 h after which time TLC analysis showed consumption of

starting material. The reaction mixture was quenched by addition of

pH 7 buffer (1 mL), MeOH (1 mL) and then 30% H₂O₂(0.5 mL) was

added and the resulting mixture stirred at r.t. for 1 h, whereupon it was

partitioned between H₂O (5 mL) and CH₂Cl₂(3 × 5 mL). The com-

bined organic extracts were dried (Na₂SO₄), concentrated in vacuo

and column chromatography (10% MeOH in CHCl₃) afforded (–)-

ACRL toxin IIIB (7) and 7-epi-7 as an 89:11 mixture (6.4 mg, 94%).

Recrystallisation (EtOAc) gave pure 7 (5.6 mg, 82%); mp 153–155°C

(Lit.^23a152°C); [α]_D–47.0 (c = 0.6, CHCl₃).

(7) For related, B-mediated, aldol reactions of α-siloxy ethyl

ketones, see:

Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B.

J. Am. Chem. Soc. 1981, 103, 1566.

Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heath-

cock, C. H. J. Org. Chem. 1991, 56, 2499.

For related, Li- and Ti(IV)-mediated, syn-aldol reactions, see:

Chodhury, A.; Thornton, E. R. Tetrahedron 1992, 48, 5701.

Panyachotipun, C.; Thornton, E. R. Tetrahedron Lett. 1990, 30,

6001.

Chodhury, A.; Thornton, E. R. Tetrahedron Lett. 1993, 34,

2221.

IR (CHCl₃): ν = 3410 (br s), 1699 (s), 1640 cm^–1(m).

SYNTHESIS

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Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 3982.

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Kono, Y.; Gardner, J. M.; Suzuki, Y.; Takeuchi, S. Phytochemis-

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Article Doi

Polyketide synthesis using the boron-mediated, anti-aldol reactions of lactate-derived ketones: Total synthesis of (-)-ACRL toxin IIIB

DOI: 10.1055/s-1998-5929

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