Highly stereocontrolled total synthesis of β-d-mannosyl phosphomycoketide: A natural product from mycobacterium tuberculosis

Article

pubs.acs.org/joc

Highly Stereocontrolled Total Synthesis of β‑D‑Mannosyl

Phosphomycoketide: A Natural Product from Mycobacterium

tuberculosis

Nan-Sheng Li,*^,†Louise Scharf,^†,§Erin J. Adams,^†and Joseph A. Piccirilli*^,†,‡

‡

^†Department of Biochemistry and Molecular Biology and Department of Chemistry, University of Chicago, 929 East 57th Street,

Chicago, Illinois 60637, United States

S

* Supporting Information

ABSTRACT: β-D-Mannosyl phosphomycoketide (C₃₂-MPM), a naturally occurring glycolipid found in the cell walls of

Mycobacterium tuberculosis, acts as a potent antigen to activate T-cells upon presentation by CD1c protein. The lipid portion of

C₃₂-MPM contains a C₃₂-mycoketide, consisting of a saturated oligoisoprenoid chain with ﬁve chiral methyl branches. Here we

develop several stereocontrolled approaches to assemble the oligoisoprenoid chain with high stereopurity (>96%) using Julia−

Kocienski oleﬁnations followed by diimide reduction. By careful choice of oleﬁnation sites, we could derive all chirality from a

single commercial compound, methyl (2S)-3-hydroxy-2-methylpropionate (>99% ee). Our approach is the ﬁrst highly

stereocontrolled method to prepare C₃₂-MPM molecule with >96% stereopurity from a single >99% ee starting material. We

anticipate that our methods will facilitate the highly stereocontrolled synthesis of a variety of other natural products containing

chiral oligoisoprenoid-like chains, including vitamins, phytol, insect pheromones, and archaeal lipids.

hydrogenation.¹¹In 2006, van Summeren et al. reported the

synthesis of C₃₂-MPM in enantiomerically enriched form via

INTRODUCTION

■

Major histocompatibility complex (MHC) class I, MHC class

II, and CD1 are three important antigen-presenting systems

Julia−Kocienski couplings of chiral building blocks containing

one or two methyl branches and palladium-catalyzed hydro-

that function to display structurally diverse antigens. Whereas

genations.¹²The chiral building blocks derive from conjugate

classical MHC proteins bind peptides and glycopeptides, CD1

addition of methylmagnesium bromide to α,β-unsaturated

proteins bind lipids speciﬁcally.¹⁻⁶Five homologous isoforms,

carbonyl thioester¹²and from conjugate addition of dimethyl-

CD1a, CD1b, CD1c, CD1d, and CD1e, comprise the human

zinc to cycloocta-2,7-dienone¹³in the presence of chiral

CD1 family.⁷Among the lipids presented by CD1c are β-D-

phosphorus ligands. This synthetic approach reportedly gave

mannosyl phosphomycoketides (C₃₀₋₃₄-MPMs), which were

C₃₂-mycoketide containing only trace amounts of diastereo-

isolated in 2000 from the cell walls of M. tuberculosis and M.

avium.⁸Biosynthesized via the action of polyketide synthase

meric impurities, attributed to the relatively low enantiose-

12,⁹these MPMs contain single alkyl chains that have ﬁve

lectivity (93% ee) of the conjugate addition of methylmagne-

methyl branches with (S)-conﬁguration.¹⁰T cells reactive to

sium bromide to α,β-unsaturated carbonyl thioester that was

carried through the synthesis.^12,14However, Curran and co-

CD1c presenting MPM secrete IFN-γ, an important cytokine in

the immunological response against M. tuberculosis.^8,9We were

workers recently demonstrated that the stereopurity of C₃₂-

mycoketide prepared in this manner has only modest

interested in obtaining a sizable amount of C₃₂-MPM (Figure

1) in stereopure form for use in co-crystallization with CD1c.

stereopurity (∼70%).¹⁵This low stereopurity of the mycoke-

tide is possiblly due to both stereochemical heterogenity of the

When we initiated this work, CD1c was the only member of the

building blocks and epimerization that likely occurred during

human CD1 family for which no crystal structure was available.

palladium catalyzed hydrogenation.¹⁶Analogous hydrogenation

Isolation from natural sources has produced exceedingly low

yields of C₃₂-MPM, but total chemical synthesis has provided

useful quantities of these antigenic lipids and several derivatives

reactions described here underscore the latter concern.

We report several new synthetic strategies to prepare C₃₂-

mycoketide with signiﬁcantly higher stereopurity than reported

thereof, enabling analysis of structural features that confer a T-

previously. In contrast to the existing approaches,¹²which

required multiple conjugate addition reactions involving

cell response.^8,10Two previous reports on the synthesis of

MPM compounds have appeared in literature.^11,12In 2002,

Crich and Dudkin reported a stereorandom synthesis of C₂₀₋₃₀

-

MPMs, starting from geranyl acetate, via coupling of planar

Received: March 28, 2013

alkene precursors and subsequent Adams (PtO₂) catalytic

A

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Figure 1. Examples of natural products containing saturated 1,5-dimethyl alkyl subunits.

diﬀerent starting materials, all chiral fragments used in this work

derive from a single commercially available chiral substrate,

methyl (2S)-3-hydroxy-2-methylpropionate (1) (>99.0% ee).

In addition, our synthetic approach circumvents the formation

of diastereomeric impurities. Crystallization of CD1c loaded

with our synthetic C₃₂-MPM ligand yielded a 2.5 Å crystal

structure of the complex.¹⁷In addition to enabling facile

synthesis of other MPM derivatives and stereoisomers, we

anticipate that our synthetic strategies will facilitate the

synthesis of other natural products containing 1,5-dimethyl

alkyl subunits (Figure 1), such as vitamins (I, II),^18,19phytol

(III),²⁰insect pheromones (IV−VIII),²¹⁻²⁹and archaeal lipids

(IX−XI).³⁰⁻³⁵

2-methylpropionate (1). Additionally, this adjustment would

circumvent the conjugate addition reaction that putatively

limited the overall stereopurity in the previous approach.¹²We

evaluated three diﬀerent strategies for the synthesis of C₃₂-

mycoketide using N-phenyltetrazolyl sulfone (9) as the C₁₋₅

fragment, an unsaturated aldehyde (17 or 32) as the C₆₋₁₃

fragment, and an N-phenyltetrazolyl sulfone (22 or 39) or

aldehyde 32 as the C₁₄₋₂₀₊fragment (Figure 2, Methods A, B

and C).

RESULTS AND DISCUSSION

■

Method A: Synthesis of C₃₂-Mycoketide (83% Stereo-

purity) by the Coupling of Fragments 9, 17, and 22

Followed by Pt/Pd-Catalyzed Hydrogenations (Schemes

1−4). 1. Synthesis of the C₁₋₅Fragment: β-Methylalkyl N-

Phenyltetrazolyl Sulfone 9 (Scheme 1). Nicolaou et al.³⁸have

prepared 7 in seven steps from methyl (2S)-3-hydroxy-2-

methylpropionate (1) in 52% overall yield. Using the same

starting material 1, we developed an alternative synthetic

approach to alcohol 7 in nine steps (57% overall yield)

(Scheme 1). Compound 1 allowed access to enantiomerically

pure (3R)-4-(tert-butyldiphenylsiloxy)-3-methylbutanal (3)^39,40

in ﬁve steps (81% yield). Wittig reaction or Julia−Kocienski

oleﬁnation of aldehyde 3 gave terminal alkene 4 in 81% yield.

Retrosynthetic Analysis. Previous work¹²has shown that

Julia−Kocienski oleﬁnations^36,37followed by hydrogenation

enabled access to the C₃₂-mycoketide from three appropriately

derivatized fragments corresponding to C₁₋₆, C₇₋₁₄, and C₁₅₋₂₀₊

(see top of Figure 2 for carbon numbering scheme), each

containing one or two chiral methyl groups.¹²With this overall

strategy in mind, we envisioned that shifting the bond

disconnections by one unit would allow access to the C₃₂-

mycoketide via three fragments (corresponding to C₁₋₅, C₆₋₁₃

,

and C₁₄₋₂₀₊), which could be derived from the same

commercially available chiral source, methyl (2S)-3-hydroxy-

B

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Figure 2. Retrosynthetic analysis of C₃₂-MPM.

Scheme 1. Synthesis of β-Methylalkyl N-Phenyltetrazolyl Sulfone 9

C

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Scheme 2. Synthesis of 4,5-Unsaturated Aldehyde 17

Scheme 3. Synthesis of 3,7-Dimethylalkyl N-Phenyltetrazolyl Sulfone 22 (86% de)

Successive hydroboration of 4 with 9-BBN followed by

oxidation with sodium perborate⁴¹gave alcohol 5 in

quantitative yield. Subsequent benzyl protection and desilyla-

tion converted alcohol 5 into monobenzyl protected alcohol 7

in 92% and 95% yields, respectively. To convert compound 7 to

9, a two-step substitution−oxidation sequence was employed.

Compound 7 was ﬁrst reacted with 1-phenyl-1H-tetrazole-5-

thiol (PT-SH) under Mitsunobu conditions, followed by

oxidation with 3-chloroperoxybenzoic acid (m-CPBA)⁴²to

generate the N-phenyltetrazolyl sulfone 9 in 94% yield (two

steps).

2. Synthesis of the C₆₋₁₃Fragment: (2R,6R)-2,6-Dimethyl-

4,5-unsaturated Aldehyde 17 (Scheme 2). Similar to the

synthesis of sulfone 9, we prepared sulfone 14 from the

corresponding monobenzyl protected alcohol 12. Substituting

TBDPS for TBS to protect the hydroxyl group in 1, the

procedure outlined by Dandapani et al.⁴³was used to form the

monobenzyl protected alcohol 12 in slightly higher overall yield

than what was previously reported (i.e., 54% yield versus 46%;

Scheme 2). PT-SH substitution followed by m-CPBA oxidation

converted 12 into the N-phenyltetrazolyl sulfone 14 in 95%

yield. Julia−Kocienski oleﬁnation of aldehyde 3 with sulfone 14

in the presence of lithium hexamethyldisilazide yielded alkene

15 in 78% yield as a mixture of (E/Z 3:1)-isomers. The

oleﬁnation yield improved in the presence of excess sulfone 14,

which could be recovered by silica gel chromatography during

product puriﬁcation. Desilylation of 14 with TBAF followed by

oxidation with Dess−Martin periodinane (1.2 mol equiv, 3 h)

gave the α-methyl-4,5-unsaturated aldehyde 17 in 91% yield.⁴⁴

3. Synthesis of the C₁₃₋₂₀₊Fragment: (3S,7S)-3,7-

Dimethyltetradecyl N-Phenyltetrazolyl Sulfone 22 (86% de)

(Scheme 3). Reaction of alcohol 16 with TsCl in pyridine

yielded the corresponding tosylate 18 in 95% yield. Chain

elongation of 18 with hexylmagnesium bromide in the presence

of copper(I) bromide-dimethyl sulﬁde yielded 19 in 77% yield.

Catalytic hydrogenation of 19 with 10% palladium on active

carbon reduced the double bond and removed the benzyl group

to give 3,7-dimethyltetradecanol (20). Analysis of ¹³C NMR

data for the hydrogenation product indicated that during the

reduction reaction, 30% α-epimerization occurred at C-3.

Metal-catalyzed hydrogenations of alkenes are known to cause

α-epimerization through reversible hydrometalation.^43,45,46

Catalytic hydrogenation with platinum reportedly gave

products with less isomerization than catalytic hydrogenation

with palladium.¹⁶Using 10% platinum on active carbon,

hydrogenation of 19 reduced the double bond as expected, but

access to the alcohol 20 required a second, palladium-catalyzed

hydrogenation to remove the benzyl group. This two-step

procedure gave compound 20 in 74% yield with only 7%

epimerization. The PT-SH substitution/m-CPBA oxidation

D

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Scheme 4. Method A: Synthesis of C₃₂-Mycoketide (83% Stereopurity)

sequence converted alcohol 20 into (3S,7S)-3,7-dimethylte-

tradecyl N-phenyltetrazolyl sulfone 22 (86% de) in 93% yield

(Scheme 3).

bromide-dimethyl sulﬁde complex gave the benzyl ether 30

in 84% yield. Following debenzylation with palladium-catalyzed

hydrogenation, we converted the stereopure syn,syn-3,7-

dimethyl-1-tetradecanol 20 into stereopure N-phenyltetrazolyl

sulfone 22 according to the method described in Scheme 3

(93% yield, two steps).

2. Synthesis of the C₆₋₁₃Fragment: Saturated Aldehyde

32. We prepared aldehyde 32 from the stereopure chiral

substrate 27 in two steps (Scheme 5). Debenzylation of 27 by

palladium-catalyzed hydrogenation gave stereopure alcohol 31

in 93% yield. Attempts to obtain 31 directly from 15 by

palladium-catalyzed hydrogenation and debenzylation gave only

64% yield of product with only 87% stereopurity (74% de).

Clearly, the diimide reduction procedure circumvented the

epimerization issue. Oxidation of 31 with either NMO-oxide/

TPAP⁴⁹or Dess−Martin periodinane gave the corresponding

aldehyde 32 in 69% and 97% yield, respectively.

3. Synthesis of C₃₂-Mycoketide (>96% Stereopurity) by

Coupling of Fragments 9, 22, and 32 (Scheme 5). Julia−

Kocienski coupling of aldehyde 32 with sulfone 9 gave alkene

33 in 70% yield. Desilylation of 33 with TBAF followed by

oxidation with NMO-oxide/TPAP or Dess−Martin period-

inane gave the corresponding aldehyde 35 in 72% and 90%

yield, respectively. A second Julia−Kocienski coupling of

aldehyde 35 to stereopure sulfone 22 produced the

pentamethyl substituted diene 36 in 80% yield. Subsequent

reduction of 36 with diimide generated the benzyl alkyl ether

37 in 86% yield. Finally, debenzylation of 37 by palladium-

catalyzed hydrogenation gave 93% yield of C₃₂-mycoketide

(>96% stereopurity) (Figure 3B).

Method C: Synthesis of C₃₂-Mycoketide (∼96%

Stereopurity) by Coupling of Fragments 9, 32, and 39

(C-1) or 9, 32, and 32 (C-2) (Scheme 6). 1. Method C-1:

Synthesis by the Coupling of Fragments 9, 32, and 39. We

converted the dimethyl-substituted alcohol 31 to the

corresponding N-phenyltetrazolyl sulfone 39 in two steps

(86% yield) (Scheme 6). Julia−Kocienski coupling of 39 to the

trimethyl substituted unsaturated aldehyde 35 in the presence

of LiHMDS gave the pentamethyl substituted diene 40 in 65%

yield.

4. Synthesis of C₃₂-Mycoketide (83% Stereopurity) by the

Coupling of Fragments 9, 17, and 22 (86% de) Followed by

Pt/Pd-Catalyzed Hydrogenation (Scheme 4). Julia−Kocienski

coupling of α-methyl-aldehyde 17 with sulfone 22 (86% de)

gave diene 23 in 78% yield, corresponding to a C₆₋₂₀₊segment.

Using the two-step platinum- and, later, palladium-mediated

hydrogenation procedure developed for the synthesis of 20, we

converted diene 23 to the saturated alcohol 24 in 76% yield.

Oxidation of 24 with Dess−Martin periodinane generated

aldehyde 25 in 81% yield. Julia−Kocienski coupling of aldehyde

25 with sulfone 9 yielded alkene 26 in 81% yield. Hydro-

genation of 26, ﬁrst using platinum and then using palladium as

catalysts, gave C₃₂-mycoketide in 73% yield and 83%

stereopurity, which was estimated by a recently published ¹³C

NMR method (Figure 3A).¹⁵The complicated ¹³C NMR

spectrum suggested that further epimerization might have

occurred in the platinum-catalyzed hydrogenation reactions of

23 and 26 (Scheme 4). Accordingly, we sought to eliminate

epimerization by developing an approach that avoids the metal-

catalyzed hydrogenation steps.

Method B: Total Synthesis of C₃₂-Mycoketide (>96%

Stereopurity) by Coupling of Sulfone 9, Saturated

Aldehyde 32, and Stereopure Sulfone 22 Followed by

Diimide Reduction (Scheme 5). 1. Synthesis of the

Stereopure C₁₃₋₂₀₊Fragment: (3S,7S)-3,7-Dimethyltetradecyl

N-Phenyltetrazolyl Sulfone 22 via Diimide Reduction.

Diimide (HNNH), a widely investigated reagent in organic

synthesis, oﬀered an attractive alternative for alkene reduction,

as the proposed reaction mechanism involves a cyclic transition

state that precludes epimerization.^47,48We carried out

reduction reactions with alkene 15 under a variety of conditions

and obtained the best results with 100 equiv of hydrazine and

10% copper(II) sulfate in ethanol at 70 °C for 15 h. These

conditions converted 15 into the stereopure 27 in 97% yield

with no detectable epimerization (Scheme 5). Desilylation

followed by tosylation converted 27 to tosylate 29 in high yield

(89%). Extension of the alkyl chain by coupling with

hexylmagnesium bromide in the presence of copper(I)

E

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Figure 3. Mycoketide purities were estimated by integration of the ¹³C NMR peaks. (A) Method A: 83% stereopurity, (B) Method B: 96%

stereopurity, and (C) Method C: 95−97% stereopurity.

2. Method C-2: Synthesis by Coupling of Fragments 9, 32,

and 32. We also converted unsaturated alcohol 34 to the

trimethyl substituted N-phenyltetrazolyl sulfone 43 in three

steps (61% yield, Scheme 6). Julia−Kocienski coupling of 43

with dimethyl-substituted aldehyde 32 gave the pentamethyl

substituted alkene 44 in 56% yield.

3. Synthesis of C₃₂-Mycoketide (∼96% Stereopurity) from

Pentamethyl-Substituted Alkenes 40 and 44. Reduction of 40

and 44 with diimide gave 45 in 96% and 78% yield,

respectively. Removal of the TBDPS group of 45 with TBAF

followed by tosylation and coupling with Grignard reagent

(hexylmagnesium bromide or butylmagnesium chloride) gave

the stereopure benzyl alkyl ethers 37 and 37a in 85% and 91%

F

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Scheme 5. Method B: Synthesis of Stereopure C₃₂-Mycoketide (>96% Stereopurity)

yield, respectively (Scheme 6). Finally, debenzylation of

compound 37 aﬀorded the C₃₂-mycoketide in 93% yield and

∼96% stereopurity (Figure 3C). Installation of the terminal

alkyl tail at the last stage renders this approach attractive for

accessing other mycoketides. For example, copper-catalyzed

coupling of the tosylate 47 with butylmagnesium chloride

would generate the C₃₀-mycoketide.

Synthesis of C₃₂-MPM from C₃₂-Mycoketide (Scheme

7). We converted the C₃₂-mycoketide prepared from Methods

B or C to the C₃₂-MPM molecule in two steps (83% yield)

according to literature procedures¹²with some modiﬁcations.

In the ﬁrst step, we added DMAP to accelerate the reaction and

decreased the reaction time from 4 days to 2 days. The

procedure to prepare the ﬁnal product C₃₂-MPM is described

in detail in the Experimental Section.

Curran and co-workers.¹³As shown in Figure 3, we observed

ﬁve large peaks corresponding to the ﬁve chiral methyl groups

of the mycoketide and ﬁve small peaks corresponding to the

methyl groups of its stereoisomer. By integration of those peaks

we estimated that Method A gave C₃₂-mycoketide with 83%

stereopurity, while Methods B and C gave C₃₂-mycoketide

with 96% stereopurity. Most likely the measurement of 4%

stereoimpurities derives partially from the method errors and

the <0.5% stereoimpurity of the starting material, which would

be enriched after total synthesis.

CONCLUSIONS

■

We have described several strategies to obtain C₃₂-MPM with

up to 96% stereopurity. Using methyl (2S)-3-hydroxy-2-

methylpropionate (1) (>99.0% ee) as the sole source of

chirality, we constructed chiral building blocks corresponding

to three separate fragments and connected them via Julia−

Kocienski oleﬁnations. Subsequent reduction of the double

bonds with diimide allowed access to the target molecules while

Analysis of the Stereopurity of C₃₂-Mycoketide, Key

Precursor to C₃₂-MPM. To analyze the stereoisomer

impurities of our C₃₂-mycoketides derived from Methods A,

B, and C, we used a recently published ¹³C NMR method of

G

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Scheme 6. Method C: Synthesis of Stereopure C₃₂-Mycoketide (∼96% Stereopurity)

Scheme 7. Synthesis of C₃₂-MPM from C₃₂-Mycoketide

preserving the stereochemical integrity of the chiral centers.

Although the approach bears some similarities to the approach

of van Summeren et al.¹²and requires a similar number of

steps, several relatively simple changes described in this work

allow access to C₃₂-mycoketide in higher yield (Method B)

and with greater stereopurity than reported previously. First, by

shifting bond disconnections by one unit we are able to use a

single, commercially available chiral source. In the previous

synthesis of C₃₂-mycoketide, access to the chiral building

blocks alone required substantial eﬀort and included multiple

conjugate addition reactions in the presence of chiral

ligands.^12,13One of those reactions proceeded with relatively

low stereoselectivity (93% ee). Second, our use of diimide

instead of catalytic hydrogenation to accomplish the reductions

following oleﬁnation has completely eliminated the epimeriza-

tion problem that likely corrupted stereochemical integrity in

the previous synthesis. Our approach represents the only highly

stereocontrolled approach to prepare the C₃₂-MPM molecule

with up to 96% stereopurity from >99% ee starting material.

Additional beneﬁts of our approach include relatively

straightforward access to β-C₃₂-MPM stereoisomers and

other mycoketide derivatives. Both methyl (2R)- and (2S)-3-

hydroxy-2-methylpropionate are commercially available

(>99.0% ee) and can serve as chiral precursors to prepare

stereopure forms of any of the 32 C₃₂-MPM stereoisomers via

Methods B and C. Method C installs the straight-chain alkyl

group at a late stage, allowing convenient preparation of other

mycoketide derivatives from intermediate 47 (Scheme 6). The

H

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acetate in hexane to give 5 as an oil:^38,602.22 g, (100% yield). H

1

facile synthesis of other MPM molecules such as C₃₀-MPM and

the MPM stereoisomers may allow detailed functional analysis

of how CD1c protein binds to various natural and unnatural

MPMs that may activate, partially activate, or deactivate T-cells.

The ability to produce highly stereopure methyl branched

isoprenoid chains may also be applied to the total synthesis of

other natural products containing 1,5-dimethyl alkyl subunits

(Figure 1) including archaeal lipids, which have garnered great

attention recently for biotechnology applications.⁵⁰⁻⁵⁸

NMR (CDCl₃/TMS) δ 7.70−7.64 (m, 4H), 7.43−7.32 (m, 6H),

5.82−5.68 (m, 1H), 5.04−4.92 (m, 2H), 3.49 (m, 2H), 2.26 (m, 1H),

1.91 (m, 1H), 1.76 (m, 1H), 1.06 (s, 9H), 0.91 (d, 3H, J = 6.8 Hz);

¹³C NMR (CDCl₃) δ 135.6, 134.0, 129.5, 127.6, 68.7, 63.3, 35.5, 30.2,

29.1, 26.9, 19.3, 16.8.

(2R)-1-(tert-Butyldiphenylsilyloxy)-2-methyl-5-benzoxypen-

tane (6). Under argon to a solution of (4R)-5-(tert-butyldiphenylsi-

lyloxy)-4-methyl-1-petanol (5) (0.235 g, 0.659 mmol) in anhydrous

THF (5 mL) at 0 °C was added NaH (50.0 mg, 95%, 1.98 mmol).

After the mixture was stirred at 0 °C for 10 min, benzyl bromide (339

mg, 1.98 mmol) was added, and the reaction mixture was stirred at rt

overnight. The reaction was quenched with saturated aqueous NH₄Cl,

and the aqueous layer was extracted with Et₂O. The solvent was

removed under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with 1% ethyl acetate in hexane to give 6 as

an oil: 0.270 g (92% yield). H NMR (CDCl₃/TMS) δ 7.70−7.63

(m, 4H), 7.44−7.22 (m, 11H), 4.49 (s, 2H), 3.52 (dd, 1H, J = 6.0, 9.6

Hz), 3.47−3.40 (m, 3H), 1.72−1.59 (m, 2H), 1.59−1.45 (m, 2H),

1.19 (m, 1H), 1.05 (s, 9H), 0.93 (d, 3H, J = 6.4 Hz); ¹³C NMR

(CDCl₃) δ 138.8, 135.8, 134.2, 129.6, 128.5, 127.72, 127.70, 127.6,

73.0, 70.9, 69.0, 35.8, 29.8, 27.4, 27.0, 19.5, 17.0.

EXPERIMENTAL SECTION

■

(3R)-4-(tert-Butyldiphenylsilyloxy)-3-methylbutanenitrile

(2). (62.0 g, 87% yield) Prepared from methyl (2S)-3-hydroxy-2-

methylpropionate (1) (25.0 g, 212 mmol) in four steps according to

literature procedure.^39,40¹H NMR (CDCl₃/TMS) δ 7.68−7.60 (m,

4H), 7.48−7.36 (m, 6H), 3.63 (dd, 1H, J = 4.4, 10.0 Hz), 3.47 (dd,

1H, J = 7.2, 10.0 Hz), 2.56 (dd, 1H, J = 5.6, 16.8 Hz), 2.38 (dd, 1H, J =

7.6, 16.8 Hz), 2.08 (m, 1H), 1.06 (s, 9H), 1.03 (d, 3H, J = 6.5 Hz); ¹³C

NMR (CDCl₃) δ 135.67, 135.64, 133.32, 133.26, 130.0, 127.9, 119.0,

67.0, 33.4, 27.0, 21.2, 19.4, 16.0.

6

1

(3R)-4-(tert-Butyldiphenylsilyloxy)-3-methylbutanal (3).

(12.0 g, 93% yield) Prepared from (3R)-4-(tert-butyldiphenylsily-

loxy)-3-methylbutanenitrile (2) (12.8 g, 37.9 mmol) according to

literature procedure.^39,40¹H NMR (CDCl₃/TMS) δ 9.78 (dd, 1H, J =

2.0, 2.4 Hz), 7.70−7.60 (m, 4H), 7.48−7.30 (m, 6H), 3.58 (dd, 1H, J

= 5.2, 10.0 Hz), 3.43 (dd, 1H, J = 7.2, 10.0 Hz), 2.60 (ddd, 1H, J = 2.0,

5.6, 15.8 Hz), 2.40−2.20 (m, 2H), 1.05 (s, 9H), 0.94 (d, 3H, J = 6.8

Hz); ¹³C NMR (CDCl₃) δ 202.8, 135.70, 135.68, 133.58, 133.56,

129.8, 127.8, 68.5, 48.3, 31.4, 26.9, 19.4, 16.9.

(4R)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-1-petene (4).

A. Via Wittig Reaction. Under argon, s-BuLi (1.4 M in cyclohexane)

(21.4 mL, 30.0 mmol) was added slowly to a suspension of

triphenylmethylphosphonium bromide (10.7 g, 30.0 mmol) in

anhydrous THF (60 mL) at −78 °C. After the mixture was stirred

at −78 °C for 1 h, a solution of (3R)-4-(tert-butyldiphenylsilyloxy)-3-

methylbutanal (3) (4.09 g, 12.0 mmol) in anhydrous THF (30 mL)

was transferred to the mixture under argon. The mixture was warmed

to rt and stirred overnight. The solid was ﬁltered oﬀ and rinsed with

Et₂O. The ﬁltrate was washed with saturated aqueous NH₄Cl, and the

aqueous layer was extracted with Et₂O. The solvent was removed

under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with hexane to give 4 as an oil:⁵⁹3.24 g

(80% yield).

(2R)-2-Methyl-5-benzoxy-1-pentanol (7). TBAF (1.0 M in

THF, 3.4 mL, 3.4 mmol) was added to a solution of (2R)-1-(tert-

butyldiphenylsilyloxy)-2-methyl-5-benzoxypentane (6) (1.01 g, 2.26

mmol) in THF (5 mL). After the mixture was stirred at rt overnight,

the solvent was removed under vacuum, and the residue was puriﬁed

by silica gel chromatography, eluting with 20% ethyl acetate in hexane

to give 7 as an oil:³⁸0.445 g (95% yield). H NMR (CDCl₃/TMS) δ

1

7.40−7.20 (m, 5H), 4.50 (s, 2H), 3.49−3.40 (m, 4H), 1.81 (brs, 1H),

1.76−1.42 (m, 4H), 1.21 (m, 1H), 0.91 (d, 3H, J = 6.8 Hz); ¹³C NMR

(CDCl₃) δ 138.6, 128.5, 127.8, 127.7, 73.1, 70.8, 68.2, 35.7, 29.7, 27.2,

16.7.

5-[(2R)-5-Benzoxy-2-methylpentylsulfanyl]-1-phenyl-1H-tet-

razole (8). Under argon to a solution of (2R)-2-methyl-5-benzoxy-1-

pentanol (7) (922 mg, 4.43 mmol) and 1-phenyl-1H-tetrazole-5-thiol

(947 mg, 5.31 mmol) in anhydrous THF (15 mL) at 0 °C were added

PPh₃(1.39 g, 5.31 mmol) and DEAD (0.85 mL, 5.3 mmol). After the

mixture was stirred at rt for 1 h, the reaction was quenched with water.

The aqueous layer was extracted with Et₂O. The organic layers were

combined, and the solvent was removed under vacuum. The residue

was puriﬁed by silica gel chromatography, eluting with 10% ethyl

1

acetate in hexane to give 8 as an oil: 1.57 g (96% yield). H NMR

(CDCl₃/TMS) δ 7.60−7.50 (m, 5H), 7.36−7.23 (m, 5H), 4.49 (s,

2H), 3.50−3.43 (m, 3H), 3.27 (dd, 1H, J = 12.4, 7.2 Hz), 1.97 (m,

1H), 1.78−1.54 (m, 3H), 1.41−1.25 (m, 1H), 1.05 (d, 3H, J = 6.4

Hz); ¹³C NMR (CDCl₃) δ 154.8, 138.6, 133.8, 130.1, 129.8, 128.4,

127.7, 127.6 123.9, 73.0, 70.3, 40.5, 32.9, 32.5, 27.2, 19.1; HRMS

(ESI/APCl) calcd for C₂₀H₂₅N₄OS [MH⁺] 369.1744, found 369.1749.

5-[(2R)-5-Benzoxy-2-methylpentane-1-sulfonyl]-1-phenyl-

1H-tetrazole (9). To a solution of 5-[(2R)-5-benzoxy-2-methyl-

pentylsulfanyl]-1-phenyl-1H-tetrazole (8) (1.54 g, 4.18 mmol) in

CH₂Cl₂(50 mL) at 0 °C was added m-CPBA (77% purity, 4.69 g, 20.9

mmol). After the reaction mixture was stirred at rt overnight, 10%

aqueous Na₂S₂O₃(8.0 mL) and saturated aqueous NaHCO₃(12 mL)

were added and stirred for 30 min. The organic layer was separated,

and the aqueous layer was extracted with CH₂Cl₂(3 × 15 mL). The

organic layers were combined and subsequently washed with 10%

aqueous Na₂S₂O₃(2 × 8 mL), saturated aqueous NaHCO₃(2 × 10

mL), and brine. The solvent was removed, and the residue was puriﬁed

by silica gel chromatography, eluting with 10% ethyl acetate in hexane

to give 9 as semisolid: 1.64 g (98% yield). ¹H NMR (CDCl₃/TMS) δ

7.61 (m, 2H), 7.51 (m, 3H), 7.35−7.20 (m, 5H), 4.46 (s, 2H), 3.77

(dd, 1H, J = 14.5, 4.5 Hz), 3.54 (dd, 1H, J = 14.5, 7.5 Hz), 3.44 (m,

2H), 2.32 (m, 1H), 1.70−1.55 (m, 1H), 1.43 (m, 1H), 1.12 (d, 3H, J =

7.0 Hz); ¹³C NMR (CDCl₃) δ 153.9, 138.2, 132.9, 131.2, 129.4, 128.2,

127.43, 127.37, 125.0, 72.7, 69.7, 61.5, 32.9, 28.0, 26.4, 19.4; HRMS

(ESI/APCl) calcd for C₂₀H₂₅N₄O₃S [MH⁺] 401.1642, found

401.1641.

B. Via Julia−Kocienski Oleﬁnation. Under argon, LiHMDS (0.50

M in THF, 17.0 mL, 8.50 mmol) was added in a dropwise fashion over

30 min to a solution of 5-(methanesulfonyl)-1-phenyl-1H-tetrazole

(1.80 g, 8.01 mmol) and (3R)-4-(tert-butyldiphenylsilyloxy)-3-

methylbutanal (3) (2.72 g, 7.99 mmol) in anhydrous THF (70 mL)

at −78 °C. The resulting yellow solution was stirred at −78 °C for 3 h

and then allowed to warm to rt overnight. The reaction was quenched

with saturated aqueous NH₄Cl (20 mL), and the aqueous layer was

extracted with Et₂O (3 × 35 mL). The solvent was removed under

vacuum, and the residue was puriﬁed by silica gel chromatography,

eluting with hexane to give 4 as an oil:⁵⁹2.19 g (81% yield). ¹H NMR

(CDCl₃/TMS) δ 7.70−7.64 (m, 4H), 7.43−7.32 (m, 6H), 5.82−5.68

(m, 1H), 5.04−4.92 (m, 2H), 3.49 (m, 2H), 2.26 (m, 1H), 1.91 (m,

1H), 1.76 (m, 1H), 1.06 (s, 9H), 0.91 (d, 3H, J = 6.8 Hz); ¹³C NMR

(CDCl₃) δ 137.3, 135.7, 134.1, 129.6, 127.7, 115.8, 68.4, 37.7, 35.8,

27.0, 19.4, 16.5.

(4R)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-1-petanol (5).

Under argon, 9-BBN (2.27 g, 9.30 mmol) was added to a solution

of (4R)-5-(tert-butyldiphenylsilyloxy)-4-methyl-1-petene (4) (2.11 g,

6.23 mmol) in anhydrous THF (25 mL). The reaction mixture was

stirred at rt overnight. Water (15 mL) and NaBO₃·4H₂O (8.59 g, 55.8

mmol) were added, and the mixture was stirred at rt for 2 h. The

organic layer was separated, and the aqueous layer was extracted with

Et₂O (3 × 15 mL). The organic layers were combined and washed

with brine. The solvent was removed under vacuum, and the residue

was puriﬁed by silica gel chromatography, eluting with 15% ethyl

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(3R)-4-(tert-Butyldiphenylsilyloxy)-3-methyl-1-butanol (10).

To a solution of (3R)-4-(tert-butyldiphenylsilyloxy)-3-methylbutanal

(3) (11.5 g, 33.7 mmol) in a mixed solvent of methanol/water (10:1,

v/v) (150 mL) at 0 °C was added slowly sodium borohydride (3.19 g,

84.3 mmol). After the mixture was stirred at 0 °C for 1 h, the reaction

was quenched with 1 N HCl. The aqueous layer was extracted with

Et₂O. The organic layers were combined and washed with brine. The

solvent was removed, and the residue was puriﬁed by silica gel

chromatography, eluting with 15% ethyl acetate in hexane to give 10 as

= 14.8, 4.4 Hz), 3.61 (dd, 1H, J = 14.8, 8.4 Hz), 3.59−3.51 (m, 2H),

2.54 (m, 1H), 1.83 (m, 1H), 1.71 (m, 1H), 1.18 (d, 3H, J = 6.8 Hz);

¹³C NMR (CDCl₃) δ 154.1, 138.2, 133.2, 131.5, 129.8, 128.5, 127.8,

125.3, 73.2, 67.4, 61.9, 36.1, 26.4, 19.9; HRMS (ESI/APCl) calcd for

C₁₉H₂₃N₄O₃S [MH⁺] 387.1485, found 387.1490.

8-Benzoxy-1-(tert-butyldiphenylsilyloxy)-(2R,6R)-2,6-di-

methyl-4-(Z/E)-4-octene (15). Under argon, LiHMDS (0.50 M in

THF, 20.0 mL, 10.0 mmol) was added in a dropwise fashion over 30

min to a solution of 5-[(2R)-4-benzoxy-2-methyl-butane-1-sulfonyl]-1-

phenyl-1H-tetrazole (14) (3.89 g, 10.1 mmol) and (3R)-4-(tert-

butyldiphenylsilyloxy)-3-methylbutanal (3) (2.76 g, 8.11 mmol) in

anhydrous THF (100 mL) at −78 °C. The resulting yellow solution

was stirred at −78 °C for 3 h and then allowed to warm to rt

overnight. The reaction was quenched with saturated aqueous NH₄Cl,

and the aqueous layer was extracted with Et₂O (3 × 50 mL). The

solvent was removed, and the residue was puriﬁed by silica gel

chromatography, eluting with 1% ethyl acetate in hexane to give 15 as

an oil:^61,629.23 g (80% yield). H NMR (CDCl₃/TMS) δ 7.70−7.60

1

(m, 4H), 7.48−7.30 (m, 6H), 3.69 (m, 2H), 3.52 (m, 2H), 2.50 (brs,

1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.55 (m, 1H), 1.06 (s, 9H), 0.90 (d,

3H, J = 6.8 Hz); ¹³C NMR (CDCl₃) δ 135.60, 135.59, 133.5, 129.7,

127.7, 69.2, 61.2, 37.4, 33.3, 26.8, 19.2, 17.2.

(2R)-1-(tert-Butyldiphenylsilyloxy)-2-methyl-4-benzoxybu-

tane (11). Under argon, NaH (95% purity, 440 mg, 17.4 mmol) was

added to a solution of (3R)-4-(tert-butyldiphenylsilyloxy)-3-methyl-

butanol (10) (4.57 g, 13.4 mmol) in anhydrous THF (25 mL) at 0 °C.

After the mixture was stirred at 0 °C for 20 min, benzyl bromide (3.14

g, 2.18 mL) was added, and the mixture was stirred at rt overnight.

The reaction was quenched with saturated aqueous NH₄Cl, and the

aqueous layer was extracted with Et₂O. The organic layers were

combined and washed with brine. The solvent was removed under

vacuum, and the residue was puriﬁed by silica gel chromatography,

eluting with 2% ethyl acetate in hexane to give 11 as an oil:⁶²5.10 g

1

an oil: 3.16 g (78% yield). H NMR (CDCl₃/TMS) δ 7.70−7.22 (m,

15H), 5.35−5.10 (m, 2H), 4.44 (m, 2H), 3.54−3.37 (m, 4H), 2.30−

2.10 (m, 2H), 1.88−1.78 (m, 1H), 1.73−1.47 (m, 3H), 1.06 (s, 9H),

0.97−0.87 (m, 6H); ¹³C NMR (CDCl₃) δ 138.8, 137.3, 136.6, 135.8,

134.20, 134.18, 129.6, 128.4, 127.8, 127.7, 127.6, 127.3, 127.2, 73.1,

73.0, 69.0, 68.8, 68.7, 68.5, 37.4, 37.0, 36.7, 36.3, 36.2, 33.8, 31.1, 28.8,

27.0, 21.5, 21.2, 19.5, 16.9, 16.6; HRMS (ESI/APCl) calcd for

C₃₃H₄₄O₂NaSi [MNa⁺] 523.3003, found 523.3003.

1

(88% yield). H NMR (CDCl₃/TMS) δ 7.68−7.62 (m, 4H), 7.45−

8-Benzoxy-(2R,6R)-2,6-dimethyl-4-(Z/E)-4-octenol-1 (16).

TBAF (1.0 M in THF, 15 mL, 15 mmol) was added to a solution

of 8-benzoxy-1-(tert-butyldiphenylsilyloxy)-(2R,6R)-2,6-dimethyl-4-

(Z/E)-4-octene (15) (5.05 g, 10.1 mmol) in THF (20 mL). After

the mixture was stirred at rt overnight, the solvent was removed, and

the residue was puriﬁed by silica gel chromatography, eluting with 15%

7.22 (m, 11H), 4.46 (m, 2H), 3.55−3.43 (m, 4H), 1.90−1.75 (m, 2H),

1.45 (m, 1H), 1.05 (s, 9H), 0.94 (d, 3H, J = 6.8 Hz); ¹³C NMR

(CDCl₃) δ 138.80, 135.76, 134.1, 129.6, 128.5, 127.73, 127.72, 127.6,

73.0, 68.9, 68.8, 33.3, 33.1, 27.0, 19.5, 17.1.

(2R)-2-Methyl-4-benzoxy-1-butanol (12). (2R)-1-(tert-Butyldi-

phenylsilyloxy)-2-methyl-4-benzoxybutane (11) (9.55 g, 22.1 mmol)

was dissolved into THF (50 mL) and treated with TBAF (1.0 M, 33.0

mL, 33.0 mmol) at rt overnight. The solvent was removed, and the

residue was puriﬁed by silica gel chromatography, eluting with 20%

1

ethyl acetate in hexane to give 16 as an oil: 2.65 g (100% yield). H

1

NMR showed the ratio of two isomers ∼78:22. H NMR (CDCl₃/

TMS) δ 7.40−7.23 (m, 5H), 5.40−5.15 (m, 2H), 4.47 (m, 2H), 3.50−

3.32 (m, 4H), 2.35−1.40 (m, 6H), 0.98 (d, 2.35H, J = 7.0 Hz), 0.95 (d,

0.65H, J = 6.5 Hz), 0.90 (d, 0.65H, J = 6.5 Hz), 0.88 (d, 2.35H, J = 7.0

Hz); ¹³C NMR (CDCl₃) δ 138.7, 137.6, 137.0, 128.8, 128.4, 128.2,

127.7, 127.6, 127.5, 126.8, 126.7, 73.0, 68.7, 68.6, 67.9, 67.8, 37.2, 36.8,

36.5, 36.2, 36.0, 33.8, 31.0, 28.6, 21.4, 21.1, 16.6, 16.4; HRMS (ESI/

APCl) calcd for C₁₇H₂₇O₂[MH⁺] 263.2006, found 263.2003.

ethyl acetate in hexane to give 12 as an oil:⁴³4.04 g (94% yield). H

1

NMR (CDCl₃/TMS) δ 7.40−7.20 (m, 5H), 4.52 (s, 2H), 3.60−3.40

(m, 4H), 2.68 (brs, 1H), 1.80 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H),

0.92 (d, 3H, J = 5.2 Hz); ¹³C NMR (CDCl₃) δ 138.1, 128.5, 127.9,

127.8, 73.2, 68.8, 68.2, 34.2, 34.1, 17.3.

8-Benzoxy-(2R,6R)-2,6-dimethyl-4-(Z/E)-4-octenal (17).

Under argon, Dess−Martin periodinane (522 mg, 1.23 mmol) was

added to a solution of 8-benzoxy-(2R,6R)-2,6-dimethyl-(Z/E)-4-

octenol-1 (16) (0.269 g, 1.03 mmol) in anhydrous CH₂Cl₂(5 mL)

at 0 °C. After stirring at rt for 3 h, the reaction mixture was diluted

with Et₂O (20 mL). The resulting solid was ﬁltered oﬀ and rinsed with

Et₂O. The ﬁltrate was subsequently washed with 10% Na₂S₂O₃(5

mL), NaHCO₃(5 mL), and brine (5 mL) and dried over anhydrous

MgSO₄. The solvent was removed, and the residue was puriﬁed by

silica gel chromatography, eluting with 5% ethyl acetate in hexane to

give 17 as an oil: 0.242 g (91% yield). ¹H NMR (CDCl₃/TMS) δ 9.61

(m, 1H), 7.40−7.20 (m, 5H), 5.40−5.20 (m, 2H), 4.51−4.44 (m, 2H),

3.50−3.35 (m, 2H), 2.70−2.03 (m, 4H), 1.75−1.40 (m, 2H), 1.08−

0.93 (m, 6H); ¹³C NMR (CDCl₃) δ 205.0, 204.9, 138.8, 138.7, 138.0,

128.4, 127.8, 127.7, 127.6, 125.0, 124.8, 73.04, 73.00, 68.6, 68.5, 46.6,

46.3, 37.1, 36.7, 33.8, 33.7, 28.7, 28.5, 21.3, 21.0, 13.2, 13.1; HRMS

(ESI/APCl) calcd for C₁₇H₂₅O₃[M + OH]⁺277.1804, found

277.1805. The MS result indicated the aldehyde was oxidized to the

corresponding carboxylic acid.

8-Benzoxy-(2R,6R)-2,6-dimethyl-4-(E/Z)-4-octenyl p-Tolue-

nesulfonate (18). Under argon, p-TsCl (1.41 g, 7.40 mmol) was

added to a solution of 8-benzoxy-(2R,6R)-2,6-dimethyl-(Z/E)-4-

octenol-1 (16) (1.52 g, 5.79 mmol) and DMAP (5 mg) in pyridine

(10 mL) at 0 °C. After the mixture was stirred at rt overnight, TLC

showed the reaction was complete. Water (10 mL) was added, and the

mixture was extracted with Et₂O (3 × 30 mL). The organic layers were

combined and subsequently washed with 1 N HCl (20 mL), water (20

mL), saturated NaHCO₃(20 mL), and brine (20 mL). The solvent

was removed, and the residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give 18

5-[(2R)-4-Benzoxy-2-methylbutylsulfanyl]-1-phenyl-1H-tet-

razole (13). Under argon, PPh₃(6.53 g, 24.9 mmol) and DEAD (4.0

mL, 25 mmol) were added to a solution of (2R)-2-methyl-4-benzoxy-

1-butanol (12) (4.03 g, 20.7 mmol) and 1-phenyl-1H-tetrazole-5-thiol

(4.44 g, 24.9 mmol) in anhydrous THF (70 mL) at 0 °C. After the

mixture was stirred at rt for 1 h, the reaction was quenched with water,

and the aqueous layer was extracted with Et₂O. The organic layers

were combined, and the solvent was removed. The residue was

puriﬁed by silica gel chromatography, eluting with 10% ethyl acetate in

1

hexane to give 13 as an oil: 7.34 g (100% yield). H NMR (CDCl₃/

TMS) δ 7.60−7.50 (m, 5H), 7.35−7.24 (m, 5H), 4.52−4.46 (m, 2H),

3.60−3.52 (m, 2H), 3.49 (dd, 1H, J = 12.5, 6.0 Hz), 3.33 (dd, 1H, J =

12.5, 7.5 Hz), 2.16 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H), 1.06 (d, 3H,

J = 6.5 Hz); ¹³C NMR (CDCl₃) δ 154.8, 138.4, 133.8, 130.1, 129.8,

128.4, 127.7, 127.6 124.0, 73.1, 68.0, 40.5, 35.6, 30.5, 19.2; HRMS

(ESI/APCl) calcd for C₁₉H₂₃N₄OS [MH⁺] 355.1587, found 355.1592.

5-[(2R)-4-Benzoxy-2-methylbutane-1-sulfonyl]-1-phenyl-1H-

tetrazole (14). To a solution of 5-[(2R)-4-benzoxy-2-methylbutyl-

sulfanyl]-1-phenyl-1H-tetrazole (13) (7.30 g, 20.6 mmol) in CH₂Cl₂

(250 mL) at 0 °C was added m-CPBA (77% purity, 23.1 g, 103

mmol). After the reaction mixture was stirred at rt overnight, 10%

aqueous Na₂S₂O₃(40 mL) and saturated aqueous NaHCO₃(60 mL)

were added and stirred for 30 min. The organic layer was separated,

and the aqueous layer was extracted with CH₂Cl₂(3 × 75 mL). The

organic layers were combined and subsequently washed with 10%

aqueous Na₂S₂O₃(2 × 40 mL), saturated aqueous NaHCO₃(2 × 50

mL), and brine. The solvent was removed, and the residue was puriﬁed

by silica gel chromatography, eluting with 10% ethyl acetate in hexane

to give 14 as semisolid: 7.59 g (95% yield). ¹H NMR (CDCl₃/TMS) δ

7.70−7.55 (m, 5H), 7.36−7.24 (m, 5H), 4.48 (s, 2H), 4.00 (dd, 1H, J

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as an oil: 2.29 g (95% yield). ¹H NMR (CDCl₃/TMS) δ 7.78 (d, 2H, J

= 7.5 Hz), 7.37−7.23 (m, 8H), 5.25−5.13 (m, 2H), 4.53−4.40 (m,

2H), 3.92−3.82 (m, 1H), 3.82−3.75 (m, 1H), 3.47−3.30 (m, 2H),

2.55 (m, 0.45H), 2.431 (s) and 2.427 (s, 3H), 2.23 (m, 0.55H), 2.12−

1.95 (m, 1H), 1.90−1.75 (m, 2H), 1.69−1.39 (m, 2H), 0.93 (d, 1.65H,

J = 7.0 Hz), 0.91 (d, 1.35H, J = 7.0 Hz), 0.87 (d, 1.35H, J = 6.5 Hz),

0.85 (d, 1.65H, J = 6.5 Hz); ¹³C NMR (CDCl₃) δ 144.7, 138.7, 138.6,

137.8, 133.2, 129.88, 129.87, 128.4, 128.0, 127.74, 127.68, 127.56,

127.55, 125.4, 125.3, 74.6, 74.5, 73.01, 72.99, 68.6, 68.5, 37.2, 36.8,

35.7, 33.7, 33.5, 33.1, 30.6, 28.7, 21.69, 21.68, 21.3, 20.9, 16.5, 16.2;

HRMS (ESI/APCl) calcd for C₂₄H₃₃O₄S [MH⁺] 417.2094, found

417.2101.

with water. The aqueous layer was extracted with Et₂O, and the

organic layers were combined. The solvent was removed, and the

residue was puriﬁed by silica gel chromatography, eluting with 5%

1

ethyl acetate in hexane to give 21 as an oil: 1.46 g (93% yield). H

NMR (CDCl₃/TMS) δ 7.63−7.50 (m, 5H), 3.50−3.32 (m, 2H), 1.81

(m, 1H), 1.68−1.52 (m, 2H), 1.40−1.00 (m, 19H), 0.94 (d, 3H, J =

6.4 Hz), 0.88 (t, 3H, J = 6.8 Hz), 0.83 (d, 3H, J = 6.4 Hz); ¹³C NMR

(CDCl₃) δ 154.6, 133.9, 130.2, 129.9, 123.9, 37.4, 37.1, 37.0, 36.1,

32.9, 32.4, 32.0, 31.5, 30.1, 29.5, 27.2, 24.4, 22.8, 19.8, 19.3, 14.2;

HRMS (ESI/APCl) calcd for C₂₃H₃₉N₄S [MH⁺] 403.2890, found

403.2896.

5-[(3S,7S)-3,7-Dimethyltetradecanesulfonyl]-1-phenyl-1H-

tetrazole (22). To a solution of 5-[(3S,7S)-dimethyltetradecylsulfan-

yl]-1-phenyl-1H-tetrazole (21) (1.45 g, 3.61 mmol) in CH₂Cl₂(45

mL) at 0 °C was added m-CPBA (77% purity, 4.05 g, 18.1 mmol).

After the reaction mixture was stirred at rt overnight, 10% aqueous

Na₂S₂O₃(10 mL) and saturated aqueous NaHCO₃(15 mL) were

added and stirred for 30 min. The organic layer was separated, and the

aqueous layer was extracted with CH₂Cl₂(3 × 15 mL). The organic

layers were combined, and subsequently washed with 10% aqueous

Na₂S₂O₃(10 mL), saturated aqueous NaHCO₃(2 × 10 mL), and

brine. The solvent was removed, and the residue was puriﬁed by silica

gel chromatography, eluting with 10% ethyl acetate in hexane to give

1-Benzoxy-(3R,7S)-3,7-dimethyl-4-(E/Z)-4-tetradecene (19).

Under argon, hexylmagnesium bromide (2.0 M in Et₂O, 7.10 mL,

14.2 mmol) was added over 40 min to a solution of 8-benzoxy-

(2R,6R)-dimethyl-4-(E/Z)-4-octenyl p-toluenesulfonate (18) (0.736 g,

1.77 mmol) and CuBr-SMe₂(91 mg, 0.44 mmol) in dry THF (20 mL)

at −78 °C. After stirring at −78 °C for 2 h, the solution was allowed to

warm to 0 °C and stirred overnight. The reaction was quenched with

saturated aqueous NH₄Cl (20 mL). The aqueous layer was extracted

with Et₂O, and the organic layers were combined and washed with

brine. The solvent was removed, and the residue was puriﬁed by silica

gel chromatography, eluting with 1% ethyl acetate in hexane to give 19

1

22 as an oil: 1.57 g (100% yield). H NMR (CDCl₃/TMS) δ 7.75−

as an oil: 453 mg (77% yield). H NMR (CDCl₃/TMS) δ 7.35−7.23

7.55 (m, 5H), 3.73 (m, 2H), 1.96 (m, 1H), 1.77 (m, 1H), 1.64 (m,

1H), 1.40−1.00 (m, 19H), 0.97 (d, 3H, J = 6.4 Hz), 0.88 (t, 3H, J =

6.8 Hz), 0.84 (d, 3H, J = 6.4 Hz); ¹³C NMR (CDCl₃) δ 153.5, 133.1,

131.4, 129.7, 125.1, 54.3, 37.2, 37.1, 36.7, 32.7, 32.00, 31.96, 30.0, 29.4,

28.3, 27.1, 24.2, 22.7, 19.7, 19.2, 14.2; HRMS (ESI/APCl) calcd for

C₂₃H₃₉N₄O₂S [MH⁺] 435.2788, found 435.2786.

(m, 5H), 5.40−5.10 (m, 2H), 4.50 (m, 2H), 3.50−3.35 (m, 2H), 2.62

(m, 0.40 H), 2.27 (m, 0.60H), 2.06 (m, 0.40H), 1.95 (m, 0.6H), 1.81

(m, 1H), 1.72−1.35 (m, 3H), 1.35−1.18 (m, 11H), 1.08 (m, 1H),

1.00−0.80 (m, 9H); ¹³C NMR (CDCl₃) δ 138.84, 138.80, 137.0,

136.3, 128.5, 127.9, 127.79, 127.77, 127.6, 73.10, 73.08, 69.0, 68.9,

40.2, 37.4, 37.0, 36.8, 36.7, 34.9, 33.9, 33.6, 33.3, 32.1, 30.1, 29.5, 28.8,

27.3, 27.2, 22.8, 21.5, 21.3, 19.8, 19.6, 14.3; HRMS (ESI/APCl) calcd

for C₂₃H₃₉O [MH⁺] 331.2995, found 331.3003.

1-Benzoxy-(3R,7R,11S,15S)-3,7,11,15-tetramethyl-4-(E/Z)-8-

(E/Z)-decosa-4,8-diene (23) (≤93% Stereopurity). Under argon,

LiHMDS solution (0.5 M in THF, 7.2 mL, 3.6 mmol) was added in a

dropwise fashion over 30 min to a solution of 5-[(3S,7S)-3,7-

dimethyltetradecanesulfonyl]-1-phenyl-1H-tetrazole (22) (93% stereo-

purity, 1.56 g, 3.59 mmol) and 8-benzoxy-(2R,6R)-2,6-dimethyl-(Z/

E)-4-octenal (17) (658 mg, 2.53 mmol) in anhydrous THF (36 mL)

at −78 °C. The reaction mixture was stirred at −78 °C for additional 3

h and then allowed to warm to rt overnight. The reaction was then

quenched with saturated aqueous NH₄Cl (20 mL), and the aqueous

layer was extracted with Et₂O. The organic layers were combined, and

the solvent was removed. The residue was puriﬁed by silica gel

chromatography, eluting with 2% ethyl acetate in hexane to give

(3S,7S)-3,7-Dimethyl-1-tetradecanol (20). A. Method A (Prod-

uct 93% Stereopurity): From 1-Benzoxy-(3R,7S)-3,7-dimethyl-4-(E/

Z)-4-tetradecene (19) via the Two-Step Metal-Catalyzed Hydro-

genation. A suspension of 10% Pt on carbon (267 mg, 0.137 mmol)

in a solvent mixture of benzene/ethanol (1:1, v/v) (15.0 mL) was

pretreated with hydrogen by 5 vacuum-hydrogen cycles. Under

hydrogen, a solution of 19 (453 mg, 1.37 mmol) in the same solvent

mixture of benzene/ethanol (1:1, v/v) (5.0 mL) was very slowly

added. After the mixture was stirred under a hydrogen balloon at rt for

16 h, the catalyst was ﬁltered oﬀ, and the solvent was removed under

vacuum. The crude intermediate was dissolved in ethyl acetate (15

mL), and 10% Pd on carbon (146 mg, 0.137 mmol) was added. The

resulting suspension was saturated with hydrogen by 5 vacuum-

hydrogen cycles. After stirring overnight under a hydrogen balloon,

TLC showed reaction was complete. The catalyst was then ﬁltered oﬀ,

and the solvent was removed. The residue was puriﬁed by silica gel

chromatography, eluting with 15% ethyl acetate in hexane to give 20

(with 93% stereopurity) as an oil: 246 mg (74% yield). ¹³C NMR

indicated the product containing ∼7% of its isomer.

B. Method B (Product Stereopure): From 1-Benzoxy-(3S,7S)-3,7-

dimethyltetradecane (30). 10% Pd on carbon (132 mg, 0.124 mmol)

was added to a solution of 30 (412 mg, 1.24 mmol) in ethyl acetate

(30 mL). The resulting suspension was saturated with hydrogen by 5

vacuum-hydrogen cycles. After stirring overnight under a hydrogen

balloon, TLC showed reaction was complete. The catalyst was then

ﬁltered oﬀ, and the solvent was removed. The residue was puriﬁed by

silica gel chromatography, eluting with 15% ethyl acetate in hexane to

give pure 20 as an oil: 262 mg (87% yield). ¹H NMR (CDCl₃/TMS) δ

3.67 (m, 2H), 1.73 (brs, 1H), 1.59 (m, 2H), 1.42−1.00 (m, 20H),

0.92−0.82 (m, 9H); ¹³C NMR (CDCl₃) δ 61.3, 40.1, 37.6, 37.5, 37.2,

32.9, 32.1, 30.1, 29.7, 29.5, 27.2, 24.5, 22.8, 19.84, 19.78, 14.2. HRMS

(EI-GCMS) calcd for C₁₆H₃₃O [M − H]⁺241.2531, found 241.2534.

5-[(3S,7S)-3,7-Dimethyltetradecylsulfanyl]-1-phenyl-1H-tet-

razole (21). Under argon to a solution of (3S,7S)-3,7-dimethyl-1-

tetradecanol (20) (947 mg, 3.91 mmol) and 1-phenyl-1H-tetrazole-5-

thiol (837 mg, 5.31 mmol) in anhydrous THF (15 mL) at 0 °C were

added PPh₃(1.23 g, 4.69 mmol) and DEAD (0.75 mL, 4.7 mmol).

After the mixture was stirred at rt for 1 h. the reaction was quenched

1

product 23 (≤93% stereopurity) as an oil: 925 mg (78% yield). H

NMR (CDCl₃/TMS) δ 7.40−7.20 (m, 5H), 5.38−5.10 (m, 4H), 4.48

(m, 2H), 3.50−3.35 (m, 2H), 2.68−1.00 (m, 28H), 1.00−0.80 (m,

15H); ¹³C NMR (CDCl₃) δ 138.85, 138.80, 137.3, 137.1, 137.02,

136.97, 136.55, 136.46, 136.3, 136.2, 128.4, 127.8, 127.74, 127.73,

127.6, 127.5, 127.41, 127.38, 127.35, 127.29, 127.2, 127.1, 73.10,

73.05, 73.03, 68.95, 68.94, 68.85, 68.82, 40.6, 40.4, 40.20, 40.18, 37.52,

37.51, 37.47, 37.4, 37.3, 37.21, 37.17, 37.15, 37.13, 37.06, 37.01, 36.98,

35.2, 35.0, 34.94, 34.93, 33.9, 33.6, 33.33, 33.31, 32.92, 32.91, 32.90,

32.4, 32.3, 32.1, 30.1, 29.5, 28.80, 28.79, 27.2, 24.7, 24.6, 22.8, 21.54,

21.48, 21.20, 21.16, 21.0, 20.8, 20.6, 20.3, 19.9, 19.8, 19.7, 19.6, 14.3;

HRMS (ESI/APCl) calcd for C₃₃H₅₇O [MH⁺] 469.4404, found

469.4407.

(3S,7S,11S,15S)-3,7,11,15-Tetramethyl-1-decosanol (24)

(≤93% Stereopurity). A suspension of 10% Pt on carbon (103

mg, 0.0528 mmol) in a solvent mixture of benzene/ethanol (1:1, v/v)

(8.0 mL) was pretreated with hydrogen by 5 vacuum-hydrogen cycles.

Under hydrogen, a solution of 1-benzoxy-(3R,7R,11S,15S)-3,7,11,15-

tetramethyl-4-(E/Z)-8-(E/Z)-decosa-4,8-diene (23) (≤93% stereo-

purity, 249 mg, 0.531 mmol) in the same solvent mixture of benzene/

ethanol (1:1, v/v) (2.0 mL) was very slowly added. After the mixture

was stirred under a hydrogen balloon overnight, the catalyst was

ﬁltered oﬀ, and the solvent was removed. The crude intermediate was

dissolved in ethyl acetate (10 mL), and 10% Pd on carbon (140 mg,

0.132 mmol) was added. The resulting suspension was saturated with

hydrogen by 5 vacuum-hydrogen cycles. After stirring under a

hydrogen balloon overnight, the catalyst was ﬁltered oﬀ, and the

K

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solvent was removed. The residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give 24

(≤93% stereopurity) as an oil: 155 mg, (76% yield). ¹H NMR

(CDCl₃/TMS) δ 3.65 (m, 2H), 1.90 (brs, 1H), 1.68−1.50 (m, 2H),

1.45−1.00 (m, 34H), 0.93−0.80 (m, 15H); ¹³C NMR (CDCl₃) δ 61.2,

40.1, 37.7, 37.6, 37.54, 37.47, 37.2, 32.93, 32.90, 32.1, 30.1, 29.7, 29.6,

27.2, 24.6, 24.5, 22.8, 19.90, 19.88, 19.8, 14.2; HRMS (ESI/APCl)

calcd for C₂₆H₅₅O₂[M + H₂O − H] 399.4197, found 399.4198.

(3S,7S,11S,15S)-3,7,11,15-Tetramethyl-decosanal (25)

(≤93% Stereopurity). Under argon, Dess−Martin periodinane

(206 mg, 0.486 mmol) was added to a solution of (3S,7S,11S,15S)-

3,7,11,15-tetramethyl-1-decosanol (24) (≤93% stereopurity, 155 mg,

0.405 mmol) in anhydrous CH₂Cl₂(5 mL) at 0 °C. After stirring at rt

for 3 h, the reaction mixture was diluted with Et₂O (50 mL). The

resulting solid was removed by ﬁltration and rinsed with Et₂O. The

ﬁltrate was subsequently washed with 10% Na₂S₂O₃(10 mL),

NaHCO₃(10 mL), and brine (10 mL) and dried over MgSO₄. The

solvent was removed, and the residue was puriﬁed by silica gel

chromatography, eluting with 5% ethyl acetate in hexane to give 25

(≤93% stereopurity) as an oil: 0.125 g (81% yield). ¹H NMR (CDCl₃/

TMS) δ 9.76 (dd, 1H, J = 2.8, 2.0 Hz), 2.40 (ddd, 1H, J = 2.0, 3.6, 16.0

Hz), 2.22 (ddd, 1H, J = 2.4, 7.6, 16.0 Hz) 2.05 (m, 1H), 1.44−1.00

(m, 33H), 0.96 (d, 3H, J = 6.8 Hz), 0.93−0.80 (m, 12H); ¹³C NMR

(CDCl₃) δ 203.2, 51.2, 37.6, 37.53, 37.50, 37.4, 37.2, 32.93, 32.91,

32.87, 32.1, 30.1, 29.6, 28.3, 27.2, 24.6, 24.5, 22.8, 20.2, 19.92, 19.89,

19.85, 14.3; HRMS (ESI/APCl) calcd for C₂₆H₅₂O₂[M + O]⁺

396.3967, found 396.3970. The MS result indicated the aldehyde

was oxidized to the corresponding carboxylic acid.

1-Benzoxy-(4R,8S,12S,16S,20S)-4,8,12,16,20-pentamethyl-5-

(E/Z)-5-heptacosene (26) (≤93% Stereopurity). Under argon,

LiHMDS solution (0.5 M in THF, 0.80 mL, 0.40 mmol) was added in

a dropwise fashion over 3 min to a solution of 5-[(2R)-5-benzoxy-2-

methyl-pentane-1-sulfonyl]-1-phenyl-1H-tetrazole (9) (0.154 g, 0.385

mmol) and (3S,7S,11S,15S)-3,7,11,15-tetramethyl-decosanal (25)

(≤93% stereopurity, 0.125 g, 0.328 mmol) in anhydrous THF (4

mL) at −78 °C. After the reaction mixture was stirred at −78 °C for 3

h and then allowed to warm to rt overnight, the reaction was quenched

with saturated aqueous NH₄Cl, and the aqueous layer was extracted

with Et₂O. The organic layers were combined, and the solvent was

removed. The residue was puriﬁed by silica gel chromatography,

eluting with 1% ethyl acetate in hexane to give product 26 (≤93%

stereopurity) as an oil: 149 mg (81% yield). ¹H NMR (CDCl₃/TMS)

δ 7.40−7.20 (m, 5H), 5.40−5.10 (m, 2H), 4.49 (s, 2H), 3.50−3.40 (m,

2H), 2.50−1.00 (m, 41H), 1.00−0.80 (m, 18H); ¹³C NMR (CDCl₃) δ

138.9, 137.4, 136.8, 128.4, 127.73, 127.71, 127.57, 127.56, 127.51,

127.46, 72.99, 72.97, 70.8, 51.2, 40.2, 37.61, 37.58, 37.55, 37.53, 37.51,

37.4, 37.3, 37.2, 37.12, 37.08, 36.9, 34.9, 34.1, 33.7, 33.6, 33.4, 32.96,

32.95, 32.94, 32.91, 32.90, 32.1, 31.7, 30.2, 29.6, 28.4, 27.9, 27.8, 27.3,

24.7, 24.6, 22.9, 21.2, 20.2, 19.95, 19.93, 19.92, 19.87, 19.86, 19.7, 14.3;

HRMS (ESI/APCl) calcd for C₃₉H₇₁O [MH⁺] 555.5499, found

555.5502.

in THF (8 mL). After the mixture was stirred at rt overnight, the

solvent was removed, and the residue was puriﬁed by silica gel

chromatograph, eluting with 15% ethyl acetate in hexane to give

product 28 as an oil: 444 mg (100% yield). ¹H NMR (CDCl₃/TMS) δ

7.40−7.20 (m, 5H), 4.49 (s, 2H), 3.55−3.34 (m, 4H), 1.72−1.00 (m,

10H), 0.90 (d, 3H, J = 6.8 Hz), 0.87 (d, 3H, J = 6.4 Hz); ¹³C NMR

(CDCl₃) δ 138.8, 128.4, 127.7, 127.6, 73.0, 68.8, 68.4, 37.5, 36.8, 35.8,

33.5, 30.0, 24.4, 19.8, 16.7; HRMS (ESI/APCl) calcd for C₁₇H₂₉O₂

[MH⁺] 265.2162, found 265.2167.

8-Benzoxy-(2R,6S)-2,6-dimethyl-octyl p-Toluenesulfonate

(29). Under argon, p-TsCl (411 mg, 2.15 mmol) was added to a

solution of 8-benzoxy-(2R,6S)-2,6-dimethyl-1-octanol (28) (444 mg,

1.68 mmol) and DMAP (2 mg) in pyridine (5 mL) at 0 °C. After the

mixture was stirred at rt overnight, water (5 mL) was added, and the

mixture was extracted with Et₂O. The organic layers were combined,

subsequently washed with 1 N HCl (10 mL), water (10 mL), saturated

NaHCO₃(10 mL), and brine (10 mL), and then dried over MgSO₄.

The solvent was removed, and the residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give 29 as

an oil: 629 mg (89% yield). ¹H NMR (CDCl₃/TMS) δ 7.78 (dt, 2H, J

= 2.0, 8.4 Hz), 7.42−7.23 (m, 7H), 4.49 (s, 2H), 3.87 (dd, 1H, J = 5.6,

9.6 Hz), 3.79 (dd, 1H, J = 6.4, 9.6 Hz), 3.48 (m, 2H), 2.43 (s, 3H),

1.80−1.00 (m, 10H), 0.87 (d, 3H, J = 6.8 Hz), 0.83 (d, 3H, J = 6.4

Hz); ¹³C NMR (CDCl₃) δ 144.7, 138.7, 133.2, 129.9, 128.4, 128.0,

127.7, 127.6, 75.2, 73.0, 68.7, 37.2, 36.8, 33.0, 32.9, 29.8, 24.0, 21.7,

19.7, 16.6; HRMS (ESI/APCl) calcd for C₂₄H₃₄O₄NaS [MNa⁺]

441.2070, found 441.2081.

1-Benzoxy-(3S,7S)-3,7-dimethyl-tetradecane (30). Under

argon, hexylmagnesium bromide (2.0 M in Et₂O, 5.92 mL, 11.8

mmol) was added to a solution of 29 (620 mg, 1.48 mmol) along with

CuBr-SMe₂(76 mg, 0.37 mmol) in dry THF (20 mL) at −78 °C.

After stirring at −78 °C for 2 h, the mixture was allowed to warm to 0

°C and stirred overnight. The reaction was quenched with saturated

aqueous NH₄Cl, and the reaction mixture was extracted with Et₂O.

The organic layers were combined and washed with brine. The solvent

was removed under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with 1% ethyl acetate in hexane to give 30 as

an oil: 412 mg (84% yield). ¹H NMR (CDCl₃/TMS) δ 7.40−7.20 (m,

5H), 4.50 (m, 2H), 3.50 (m, 2H), 1.72−1.50 (m, 2H), 1.47−1.00 (m,

20H), 0.92−0.81 (m, 9H); ¹³C NMR (CDCl₃) δ 138.9, 128.5, 127.7,

127.6, 73.0, 68.9, 37.6, 37.5, 37.2, 36.9, 32.9, 32.1, 30.2, 30.0, 29.6,

27.2, 24.5, 22.8, 19.89, 19.86, 14.3; HRMS (ESI/APCl) calcd for

C₂₃H₃₉O [M − H]⁺331.2995, found 331.2990.

8-(tert-Butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-1-octa-

nol (31). 10% Pd on carbon (807 mg, 0.758 mmol) was added to a

solution of 8-benzoxy-1-(tert-butyldiphenylsilyloxy)-(2R,6S)-2,6-di-

methyl-octane (27) (1.91 g, 3.79 mmol) in ethyl acetate (50 mL).

The resulting suspension was saturated with hydrogen by 5 vacuum-

hydrogen cycles. After stirring overnight under a hydrogen balloon, the

catalyst was ﬁltered oﬀ, and the solvent was removed under vacuum.

The resulting residue was puriﬁed by silica gel chromatography, eluting

with 15% ethyl acetate in hexane to give stereopure 31 as an oil: 1.45 g

8-Benzoxy-1-(tert-butyldiphenylsilyloxy)-(2R,6S)-2,6-di-

methyl-octane (27). CuSO₄(62 mg, 0.39 mmol) was added to a

solution of 8-benzoxy-1-(tert-butyldiphenylsilyloxy)-(2R,6R)-2,6-di-

methyl-(Z/E)-4-octene (15) (1.96 g, 3.91 mmol) and hydrazine

(12.3 mL, 391 mmol) in ethanol (200 mL). The mixture was bubbled

with air and stirred at 70 °C for 15 h. The solution was ﬁltered, and

the ﬁltrate was evaporated. The resulting residue was extracted with

Et₂O. The organic layers were combined and washed with brine. The

solvent was removed under vacuum, and the residue was puriﬁed by

silica gel chromatography, eluting with 1% ethyl acetate in hexane to

give 27 as an oil: 1.91 g (97% yield). ¹H NMR (CDCl₃/TMS) δ 7.70−

7.64 (m, 4H), 7.45−7.23 (m, 11H), 4.49 (s, 2H), 3.55−3.39 (m, 4H),

1.70−1.00 (m, 10H), 1.05 (s, 9H), 0.91 (d, 3H, J = 6.4 Hz), 0.85 (d,

3H, J = 6.4 Hz); ¹³C NMR (CDCl₃) δ 138.8, 135.8, 134.3, 129.6,

128.5, 127.72, 127.68, 127.6, 73.0, 69.0, 68.9, 37.5, 36.9, 35.8, 33.6,

30.0, 27.0, 24.4, 19.8, 19.5, 17.1; HRMS (ESI/APCl) calcd for

C₃₃H₄₆O₂NaSi [MNa⁺] 525.3159, found 525.3157.

1

(93% yield). H NMR (CDCl₃/TMS) δ 7.69−7.64 (m, 4H), 7.45−

7.34 (m, 6H), 3.66 (m, 2H), 3.51 (dd, 1H, J = 6.0, 10.0 Hz), 3.44 (dd,

1H, J = 6.4, 10.0 Hz), 1.70−1.08 (m, 11H), 1.06 (s, 9H), 0.92 (d, 3H, J

= 6.8 Hz), 0.87 (d, 3H, J = 6.4 Hz); ¹³C NMR (CDCl₃) δ 135.8, 134.3,

129.6, 127.7, 69.0, 61.4, 40.1, 37.6, 35.9, 33.6, 29.6, 27.0, 24.4, 19.8,

19.5, 17.1; HRMS (ESI/APCl) calcd for C₂₆H₄₀O₂NaSi [MNa⁺]

435.2690, found 435.2691.

8-(tert-Butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-octanal

(32). A. Oxidation with NMO. To a solution of 8-(tert-

butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-1-octanol (31) (771 mg,

1.87 mmol) in dry CH₂Cl₂(10 mL) at 0 °C were added powdered 3 Å

molecular sieves (1.0 g), 4-methylmorpholine N-oxide (NMO) (329

mg, 2.81 mmol), and TPAP (32 mg, 0.091 mmol). The resulting

mixture was stirred at 0 °C for 30 min, then warmed to rt, and stirred

for additional 2 h. The mixture was ﬁltered through a pad of silica gel

and then washed with 50% ethyl acetate in hexane. The solvent was

removed under vacuum, and the residue was puriﬁed by silica gel

8-Benzoxy-(2R,6S)-2,6-dimethyl-1-octanol (28). TBAF (1.0 M,

8.0 mL, 4.0 mmol) was added to a solution of 27 (846 mg, 1.68 mmol)

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chromatography, eluting with 5% ethyl acetate in hexane to give 32 as

an oil: 0.529 g (69% yield).

mixture was allowed to warm to rt for 3 h until TLC showed the

reaction was complete. The mixture was diluted with Et₂O, and the

resulting solid was ﬁltered oﬀ and rinsed with Et₂O. The ﬁltrate was

subsequently washed with 10% aqueous Na₂S₂O₃, saturated aqueous

NaHCO₃, brine, and dried over anhydrous MgSO₄. The solvent was

removed, and the residue was puriﬁed by silica gel chromatography,

eluting with 5% ethyl acetate in hexane to give 35 as an oil: 949 mg

(90% yield).

B. Oxidation with Dess−Martin Periodinane. Under argon, Dess−

Martin periodinane (2.67 g, 6.30 mmol) was added to a solution of 31

(2.167 g, 5.25 mmol) in CH₂Cl₂(40 mL) at 0 °C. After stirring at 0

°C for 3 h, the mixture was diluted with Et₂O. The resulting solid was

ﬁltered oﬀ and rinsed with Et₂O. The ﬁltrate was subsequently washed

with 10% aqueous Na₂S₂O₃, saturated aqueous NaHCO₃, and brine

and dried over anhydrous MgSO₄. The solvent was removed under

vacuum, and the residue was puriﬁed by silica gel chromatography,

eluting with 5% ethyl acetate in hexane to give 32 as an oil: 2.09 g

(97% yield).

¹H NMR (CDCl₃/TMS) δ 9.60 (m, 1H), 7.40−7.20 (m, 5H),

5.40−5.10 (m, 2H), 4.49 (s, 2H), 3.50−3.40 (m, 2H), 2.50−1.10 (m,

15H), 1.10−0.80 (m, 9H); ¹³C NMR (CDCl₃) δ 205.5, 138.8, 137.7,

137.0, 128.5, 127.8, 127.7, 127.6, 127.2, 127.1, 73.0, 70.7, 46.4, 40.0,

36.9, 36.6, 36.5, 34.8, 34.0, 33.7, 33.4, 33.1, 31.7, 30.9, 27.9, 27.8, 24.6,

24.5, 21.5, 21.2, 19.8, 19.6, 13.49, 13.46; HRMS (ESI/APCl) calcd for

C₂₃H₃₇O₃[M + O − H] 361.2737, found 361.2743. The MS result

indicated the aldehyde was easily oxidized to the corresponding

carboxylic acid.

¹H NMR (CDCl₃/TMS) δ 9.73 (m, 1H), 7.69−7.64 (m, 4H),

7.45−7.34 (m, 6H), 3.55−3.40 (m, 2H), 2.34 (m, 1H), 2.19 (m, 1H),

2.02 (m, 1H), 1.65 (m, 1H), 1.50−1.00 (m, 7H), 1.06 (s, 9H), 0.95−

0.89 (m, 6H); ¹³C NMR (CDCl₃) δ 203.2, 135.7, 134.2, 129.6, 127.7,

68.9, 51.1, 37.3, 35.8, 33.3, 28.3, 27.0, 24.4, 20.1, 19.4, 17.0; HRMS

(ESI/APCl) calcd for C₂₆H₃₉O₃Si [M + OH] 427.2663, found

427.2671. The MS result indicated the aldehyde was easily oxidized to

the corresponding carboxylic acid.

1-Benzoxy-(4R,8S,12R,16S,20S)-4,8,12,16,20-pentamethyl-5-

(E/Z)-13-(E/Z)-heptacos-5,13-diene (36). Under argon, LiHMDS

solution (0.5 M in THF, 2.50 mL, 1.25 mmol) was added in a

dropwise fashion over 10 min to a solution of pure 5-[(3S,7S)-3,7-

dimethyltetradecanesulfonyl]-1-phenyl-1H-tetrazole (22) (489 mg,

1.13 mmol) and 13-benzoxy-(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-

tridecenal (35) (284 mg, 0.824 mmol) in anhydrous THF (10 mL) at

−78 °C. After the reaction mixture was stirred at −78 °C for 3 h and

then allowed to warm to rt overnight, the reaction was quenched with

saturated aqueous NH₄Cl. The aqueous layer was extracted with Et₂O,

and the organic layers were combined. The solvent was removed

under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with 1% ethyl acetate in hexane to give 36

1-Benzoxy-13-(tert-butyldiphenylsilyloxy)-(4R,8S,12R)-

4,8,12-trimethyl-5-(Z/E)-5-tridecene (33). Under argon, LiHMDS

(0.50 M in THF, 10.0 mL, 5.0 mmol) was added in a dropwise fashion

over 20 min to a solution of 5-[(2R)-5-benzoxy-2-methyl-pentane-1-

sulfonyl]-1-phenyl-1H-tetrazole (9) (1.93 g, 4.82 mmol) and 8-(tert-

butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-octanal (32) (1.794 g,

4.37 mmol) in anhydrous THF (50 mL) at −78 °C. The resulting

yellow solution was stirred at −78 °C for 3 h and then allowed to

warm to rt overnight. The reaction was quenched with saturated

aqueous NH₄Cl, and the aqueous layer was extracted with Et₂O. The

organic layers were combined, and the solvent was removed. The

residue was puriﬁed by silica gel chromatography, eluting with 1%

1

as an oil: 365 mg (80% yield). H NMR (CDCl₃/TMS) δ 7.40−7.20

1

(m, 5H), 5.40−5.10 (m, 4H), 4.49 (s, 2H), 3.50−3.35 (m, 2H), 2.50−

1.00 (m, 37H), 1.00−0.80 (m, 18H); ¹³C NMR (CDCl₃) δ 138.9,

137.9, 137.8, 137.4, 137.2, 136.8, 128.5, 127.8, 127.6, 127.53, 127.46,

127.43, 127.12, 127.06, 73.0, 70.8, 40.23, 40.19, 38.0, 37.62, 37.55,

37.2, 37.1, 37.01, 36.97, 36.9, 36.8, 35.0, 34.9, 34.1, 33.71, 33.66, 33.6,

33.4, 33.3, 32.9, 32.1, 31.8, 31.7, 30.2, 29.6, 27.9, 27.8, 27.2, 25.1, 25.0,

24.9, 24.7, 24.6, 22.9, 21.5, 21.24, 21.19, 19.90, 19.85, 19.7, 19.6, 14.3;

HRMS (ESI/APCl) calcd for C₃₉H₆₉O [MH⁺] 553.5343, found

553.5358.

ethyl acetate in hexane to give 33 as an oil: 1.79 g (70% yield). H

NMR (CDCl₃/TMS) δ 7.70−7.20 (m, 15H), 5.40−5.10 (m, 2H), 4.48

(s, 2H), 3.60−3.40 (m, 4H), 2.50−1.00 (m, 15H), 1.06 (s, 9H), 1.00−

0.80 (m, 9H); ¹³C NMR (CDCl₃) δ 138.8, 137.5, 136.8, 135.8, 134.3,

129.6, 128.4, 127.70, 127.68, 127.6, 127.5, 127.4, 73.1, 73.0, 70.7, 69.0,

40.1, 37.04, 36.98, 36.9, 35.9, 34.9, 34.1, 33.7, 33.6, 33.3, 31.7, 27.9,

27.8, 27.0, 24.6, 24.5, 21.5, 21.2, 19.9, 19.6, 19.5, 17.1; HRMS (ESI/

+

APCl) calcd for C₃₉H₆₀NO₂Si [M + NH₄] 602.4388, found 602.4393.

13-Benzoxy-(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-8-tridece-

nol-1 (34). TBAF (1.0 M in THF, 6.0 mL, 6.0 mmol) was added to a

solution of 1-benzoxy-13-(tert-butyldiphenylsilyloxy)-(4R,8S,12R)-

4,8,12-trimethyl-5-(Z/E)-5-tridecene (33) (1.79 g, 3.06 mmol) in

anhydrous THF (10 mL). After the reaction mixture was stirred at rt

overnight, the solvent was removed under vacuum, and the resulting

residue was puriﬁed by silica gel chromatography, eluting with 10−

15% ethyl acetate in hexane to give 34 as an oil: 1.06 g (100% yield).

¹H NMR (CDCl₃/TMS) δ 7.33 (m, 5H), 5.40−5.10 (m, 2H), 4.49 (s,

1-Benzoxy-(4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethyl-

heptacosane (37). A. From 1-Benzoxy-(4R,8S,12R,16S,20S)-

4,8,12,16,20-pentamethyl-5-(E/Z)-13-(E/Z)-heptacos-5,13-diene

(36). CuSO₄(10 mg, 0.0653 mmol) was added to a solution of 36

(361 mg, 0.653 mmol) and hydrazine (2.05 mL, 65.2 mmol) in

anhydrous ethanol (35 mL). After the mixture was bubbled with air

and stirred at 70 °C for 15 h, the solution was ﬁltered, and the ﬁltrate

was evaporated in vacuum. The resulting residue was then extracted

with Et₂O. The organic layers were combined and washed with brine.

The solvent was evaporated under vacuum, and the residue was

puriﬁed by silica gel chromatography, eluting with 1% ethyl acetate in

hexane to give 37 as an oil: 0.311 g (86% yield).

B. From 21-Benzoxy-(2R,6R,10R,14S,18S)-2,6,10,14,18-Pentame-

thylheneicosyl p-Toluenesulfonate (47). Under argon, hexylmagne-

sium bromide (2.0 M in Et₂O, 1.40 mL, 2.80 mmol) was added to a

solution of 47 (178 mg, 0.277 mmol) along with CuBr-SMe₂(14 mg,

0.069 mmol) in dry THF (5 mL) at −78 °C. After stirring at −78 °C

for 2 h, the mixture was allowed to warm to 0 °C and then stirred

overnight. The reaction was quenched with saturated aqueous NH₄Cl,

and the aqueous layer was extracted with Et₂O. The organic layers

were combined and washed with brine. The solvent was removed, and

the residue was puriﬁed by silica gel chromatography, eluting with 1%

ethyl acetate in hexane to give 37 as an oil: 131 mg (85% yield).

¹H NMR (CDCl₃/TMS) δ 7.40−7.20 (m, 5H), 4.51 (s, 2H), 3.45

(t, 2H, J = 6.8 Hz), 1.75−1.50 (m, 2H), 1.45−0.98 (m, 43H), 0.95−

0.82 (m, 18H); ¹³C NMR (CDCl₃) δ 138.9, 128.5, 127.8, 127.6, 73.0,

71.1, 37.6, 37.5, 37.2, 33.5, 33.0, 32.9, 32.8, 32.1, 30.2, 29.6, 27.5, 27.3,

24.6, 22.9, 20.0, 19.9, 19.8, 14.3; HRMS (ESI/APCl) calcd for

C₃₉H₇₁O [M − H]⁺555.5499, found 555.5487.

2H), 3.50−3.30 (m, 4H), 2.50−1.00 (m, 15H), 1.00−0.80 (m, 9H);

¹³C NMR (CDCl₃) δ 138.7, 137.4, 136.8, 128.4, 127.7, 127.5, 127.34,

127.29, 72.9, 70.7, 68.5, 68.4, 40.2, 40.1, 36.9, 36.8, 35.9, 35.8, 34.8,

34.0, 33.6, 33.5, 33.2, 31.7, 27.9, 27.7, 24.6, 24.5, 21.5, 21.2, 19.9, 19.7,

16.73, 16.65; HRMS (ESI/APCl) calcd for C₂₃H₃₉O₂[MH⁺]

347.2945, found 347.2947.

13-Benzoxy-(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-8-tridece-

nal (35). A. Oxidation with NMO. To a solution of 13-benzoxy-

(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-8-tridecenol-1 (34) (170 mg,

0.491 mmol) in dry CH₂Cl₂(10 mL) at 0 °C were added powdered 3

Å molecular sieves (0.25 g), NMO (86 mg, 0.73 mmol), and TPAP

(8.6 mg, 0.024 mmol). After the mixture was stirred at rt for 2 h, TLC

showed the reaction was not complete. Additional molecular sieves

(750 mg), NMO (86 mg, 0.73 mmol), and TPAP (8.6 mg, 0.024

mmol) were added. The reaction was stirred at 0 °C for an additional

30 min until TLC showed the reaction was complete. The mixture was

passed through a pad of silica gel, eluting with 5% ethyl acetate to give

35 as an oil: 121 mg (72% yield).

B. Oxidation with Dess−Martin Periodinane. Under argon, Dess−

Martin periodinane (1.56 g, 3.67 mmol) was added to a solution of 34

(1.06 g, 3.06 mmol) in dry CH₂Cl₂(25 mL) at 0 °C. The reaction

M

dx.doi.org/10.1021/jo4006602 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1-Benzoxy-(4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethyl-

pentacosane (37a). Following the procedure described for the

synthesis of 37 from 47, compound 37a was prepared from

butylmagnesium chloride (2.0 M in THF, 1.0 mL, 2.0 mmol) and

47 (115 mg, 0.179 mmol) in the presence of CuBr-SMe₂(9.2 mg,

0.045 mmol) in dry THF (5 mL). The reaction gave 37a as an oil: 86

31.8, 31.7, 27.9, 27.8, 27.0, 25.10, 25.05, 25.0, 24.9, 24.6, 24.5, 21.5,

21.2, 19.89, 19.86, 19.6, 19.5, 17.1; HRMS (ESI/APCl) calcd for

C₄₉H₇₄O₂SiK [MK⁺] 761.5090, found 761.5086.

13-Benzoxy-(2R,6R,10S)-2,6,10-trimethyl-1-tridecanol (41).

CuSO₄(6.8 mg, 0.043 mmol) was added to a solution of 13-

benzoxy-(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-tridecenol-1 (34) (149

mg, 0.430 mmol) and hydrazine (1.34 mL, 42.7 mmol) in anhydrous

ethanol (22 mL). After the mixture was bubbled with air and stirred at

70 °C for 15 h, the solution was ﬁltered, and the ﬁltrate was

evaporated under vacuum. The resulting residue was extracted with

Et₂O. The organic layers were combined and washed with brine. The

solvent was evaporated, and the residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give 41 as

an oil: 118 mg (79% yield). ¹H NMR (CDCl₃/TMS) δ 7.40−7.20 (m,

5H), 4.50 (s, 2H), 3.52−3.35 (m, 4H), 1.70−1.10 (m, 19H), 0.93−

0.82 (m, 9H); ¹³C NMR (CDCl₃) δ 138.8, 128.4, 127.7, 127.6, 73.0,

71.0, 68.4, 37.42, 37.40, 35.9, 33.6, 33.4, 32.84, 32.76, 27.4, 24.5, 19.9,

19.8, 16.8; HRMS (ESI/APCl) calcd for C₂₃H₄₁O₂[MH⁺] 349.3101,

found 349.3110.

1

mg (91% yield). H NMR (CDCl₃/TMS) δ 7.40−7.20 (m, 5H), 4.50

(s, 2H), 3.45 (t, 2H, J = 6.8 Hz), 1.75−1.50 (m, 2H), 1.45−0.98 (m,

39H), 0.93−0.82 (m, 18H); ¹³C NMR (CDCl₃) δ 138.9, 128.5, 127.7,

127.6, 73.0, 71.1, 37.6, 37.5, 37.2, 33.5, 33.0, 32.9, 32.8, 32.4, 27.5,

26.9, 24.6, 22.9, 20.0, 19.94, 19.92, 19.8, 14.3; HRMS (ESI/APCl)

calcd for C₃₇H₆₇O [M − H]⁺527.5186, found 527.5169.

5-[8-tert-Butyldiphenylsilyloxy-(3S,7R)-3,7-dimethyloctylsul-

fanyl]-1-phenyl-1H-tetrazole (38). To a solution of 8-(tert-

butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-1-octanol (31) (1.215 g,

2.94 mmol) and 1-phenyl-1H-tetrazole-5-thiol (629 mg, 3.53 mmol) in

anhydrous THF (10 mL) at 0 °C under argon were added PPh₃(926

mg, 3.53 mmol) and DEAD (0.56 mL, 3.5 mmol). The mixture was

allowed to warm to rt and stirred for 1 h. The reaction was quenched

with water, and the aqueous layer was then extracted with Et₂O. The

organic layers were combined, and the solvent was removed under

vacuum. The residue was puriﬁed by silica gel chromatography, eluting

with 10% ethyl acetate in hexane to give 38 as an oil: 1.68 g (100%

5-[13-Benzoxy-(2R,6R,10S)-2,6,10-trimethyl-1-tridecylsulfan-

yl]-1-phenyl-1H-tetrazole (42). Under argon, PPh₃(131 mg, 0.50

mmol) and DEAD (0.10 mL, 0.60 mmol) were added to a solution of

13-benzoxy-(2R,6R,10S)-2,6,10-trimethyl-1-tridecanol (41) (116 mg,

0.332 mmol) and 1-phenyl-1H-tetrazole-5-thiol (89 mg, 0.50 mmol) in

anhydrous THF (2 mL) at 0 °C. After the mixture was stirred at 0 °C

for 30 min, the reaction was quenched with water. The aqueous layer

was extracted with Et₂O, and the organic layers were combined and

dried over MgSO₄. The solvent was removed under vacuum, and the

residue was puriﬁed by silica gel chromatography, eluting with 5%

1

yield). H NMR (CDCl₃/TMS): δ 7.70−7.30 (m, 15H), 3.55−3.30

(m, 4H), 1.90−1.00 (m, 10H), 1.05 (s, 9H), 0.95−0.82 (m, 6H); ¹³C

NMR (CDCl₃) δ 154.6, 135.7, 134.2, 133.9, 130.2, 129.9, 129.6, 127.7,

124.0, 69.0, 37.0, 36.1, 35.8, 33.5, 32.3, 31.5, 27.0, 24.3, 19.4, 19.3,

17.1; HRMS (ESI/APCl) calcd for C₃₃H₄₄N₄ONaSiS [MNa⁺]

595.2897, found 595.2907.

1

5-[8-tert-Butyldiphenylsilyloxy-(3S,7R)-3,7-dimethyl-octane-

sulfonyl]-1-phenyl-1H-tetrazole (39). To a solution of 5-[8-tert-

butyldiphenylsilyloxy-(3S,7R)-3,7-dimethyl-octane-sulfanyl]-1-phenyl-

1H-tetrazole (38) (1.68 g, 2.93 mmol) in dry CH₂Cl₂(40 mL) at 0 °C

was added m-CPBA (77% purity, 3.28 g, 14.7 mmol). After the

reaction mixture was stirred at rt overnight, 10% aqueous Na₂S₂O₃(6

mL) and saturated aqueous NaHCO₃(9 mL) were added and stirred

for an additional 30 min. The organic layer was separated, and the

aqueous layer was extracted with CH₂Cl₂. The combined organic

layers were washed subsequently with 10% aqueous Na₂S₂O₃,

saturated aqueous NaHCO₃and brine. The solvent was removed

under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give 39

ethyl acetate in hexane to give 42 as an oil: 169 mg (100% yield). H

NMR (CDCl₃/TMS) δ 7.62−7.24 (m, 10H), 4.50 (s, 2H), 3.50−3.42

(m, 3H), 3.26 (dd, 1H, J = 7.6, 12.4 Hz), 1.93 (m, 1H), 1.70−1.00 (m,

18H), 1.04 (d, 3H, J = 6.4 Hz), 0.86 (d, 3H, J = 6.4 Hz), 0.84 (d, 3H, J

= 6.4 Hz); ¹³C NMR (CDCl₃) δ 154.9, 138.8, 133.9, 130.2, 129.9,

128.4, 127.7, 127.6, 124.0, 73.0, 71.0, 40.7, 37.4, 37.2, 36.4, 33.4, 33.1,

32.84, 32.78, 27.4, 24.5, 24.4, 19.84, 19.78, 19.3; HRMS (ESI/APCl)

calcd for C₃₀H₄₅N₄OS [MH⁺] 509.3309, found 509.3316.

5-[13-Benzoxy-(2R,6R,10S)-2,6,10-trimethyltridecanesulfon-

yl]-1-phenyl-1H-tetrazole (43). m-CPBA (77% purity, 3.72 mg,

1.66 mmol) was added to a solution of 5-[13-benzoxy-(2R,6R,10S)-

2,6,10-trimethyl-1-tridecylsulfanyl]-1-phenyl-1H-tetrazole (42) (169

mg, 0.332 mmol) in dry CH₂Cl₂(5 mL) at 0 °C. After the reaction

mixture was stirred at rt overnight, 10% aqueous Na₂S₂O₃(2 mL) and

saturated aqueous NaHCO₃(3 mL) were added and stirred for 30

min. The organic layer was separated, and the aqueous layer was

extracted with CH₂Cl₂. The combined organic layers were

subsequently washed with 10% aqueous Na₂S₂O₃(5 mL), saturated

aqueous NaHCO₃(3 × 5 mL), and brine. The solvent was removed

under vacuum, and the residue was puriﬁed by silica gel

chromatography, eluting with 8% ethyl acetate in hexane to give 43

1

as an oil: 1.523 g (86% yield). H NMR (CDCl₃/TMS) δ 7.74−7.33

(m, 15H), 3.81−3.62 (m, 2H), 3.50 (dd, 1H, J = 5.6, 9.6 Hz), 3.44

(dd, 1H, J = 6.0, 9.6 Hz), 2.00−1.02 (m, 10H), 1.05 (s, 9H), 0.93 (d,

3H, J = 6.8 Hz), 0.91 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃) δ 153.6,

135.7, 134.2, 133.2, 131.6, 129.8, 129.6, 127.7, 125.2, 68.9, 54.4, 36.7,

35.8, 33.4, 32.1, 28.5, 27.0, 24.2, 19.4, 19.2, 17.0; HRMS (ESI/APCl)

calcd for C₃₃H₄₄N₄O₃NaSiS [MNa⁺] 627.2796, found 627.2810.

1 - B e n z o x y - 2 1 - t e r t - b u t y l d i p h e n y l s i l y l o x y -

(4R,8S,12R,16S,20S)-4,8,12,16,20-pentamethyl-5-(E/Z)-13-(E/Z)-

heneicos-5,13-diene (40). Under argon, LiHMDS solution (0.50 M

in THF, 4.80 mL, 2.40 mmol) was added in a dropwise fashion over

20 min to a solution of 5-[8-tert-butyldiphenylsilyloxy-(3S,7R)-3,7-

dimethyl-octane-sulfonyl]-1-phenyl-1H-tetrazole (39) (1.432 mg, 2.37

mmol) and 13-benzoxy-(2R,6S,10R)-2,6,10-trimethyl-8-(Z/E)-tridece-

nal (35) (612 mg, 1.78 mmol) in anhydrous THF (25 mL) at −78 °C.

After the reaction mixture was stirred at −78 °C for 3 h and then

allowed to warm to rt overnight, the reaction was quenched with

saturated aqueous NH₄Cl, and the aqueous layer was extracted with

Et₂O. The combined organic layers were dried over anhydrous

MgSO₄. The solvent was removed, and the residue was puriﬁed by

silica gel chromatography, eluting with 1% ethyl acetate in hexane to

1

as an oil: 139 mg (77% yield). H NMR (CDCl₃/TMS) δ 7.70−7.23

(m, 10H), 4.50 (s, 2H), 3.80 (dd, 1H, J = 4.8, 14.8 Hz), 3.58 (dd, 1H, J

= 8.0, 14.4 Hz), 3.45 (t, 2H, 1H, J = 6.8 Hz), 2.33 (m, 1H), 1.70−1.00

(m, 18H), 1.15 (d, 3H, J = 6.8 Hz), 0.86 (d, 3H, J = 6.8 Hz), 0.84 (d,

3H, J = 6.4 Hz); ¹³C NMR (CDCl₃) δ 154.2, 138.8, 133.2, 131.5,

129.8, 128.4, 127.7, 127.5, 125.2, 72.9, 71.0, 60.9, 37.4, 37.0, 36.9, 33.4,

32.8, 32.7, 28.4, 27.4, 24.5, 23.9, 19.83, 19.77, 19.76; HRMS (ESI/

APCl) calcd for C₃₀H₄₅N₄O₃S [MH⁺] 541.3207, found 541.3219.

2 1 - B e n z o x y - 1 - t e r t - b u t y l d i p h e n y l s i l y l o x y -

(2R,6S,10R,14R,18S)-2,6,10,14,18-pentamethyl-8-(E/Z)-8-henei-

cosene (44). Under argon, LiHMDS solution (0.5 M in THF, 0.55

mL, 0.28 mmol) was added in a dropwise fashion over 5 min to a

solution of 5-[13-benzoxy-(2R,6R,10S)-2,6,10-trimethyltridecanesul-

fonyl]-1-phenyl-1H-tetrazole (43) (139 mg, 0.257 mmol) and 8-

(tert-butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-octanal (32) (106

mg, 0.257 mmol) in anhydrous THF (3 mL) at −78 °C. After the

reaction mixture was stirred at −78 °C for 3 h and then allowed to

warm to rt overnight, the reaction was quenched with saturated

aqueous NH₄Cl. The organic layer was separated, and the aqueous

layer was extracted with Et₂O. The combined organic layers were dried

1

give product 40 as an oil: 837 mg (65% yield). H NMR (CDCl₃/

TMS) δ 7.70−7.22 (m, 15H), 5.40−5.10 (m, 4H), 4.49 (s, 2H), 3.55−

3.40 (m, 4H), 2.50−1.00 (m, 25H), 1.06 (s, 9H), 0.98−0.80 (m,

15H); ¹³C NMR (CDCl₃) δ 138.8, 137.93, 137.88, 137.4, 137.2, 136.8,

135.8, 134.3, 129.6, 128.5, 127.71, 127.68, 127.6, 127.5, 127.4, 127.1,

127.04, 126.98, 73.0, 70.8, 69.0, 40.2, 40.1, 38.0, 37.66, 37.59, 37.1,

37.00, 36.96, 36.9, 36.8, 35.9, 35.0, 34.9, 34.1, 33.7, 33.6, 33.32, 33.30,

N

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The Journal of Organic Chemistry

Article

over anhydrous MgSO₄. The solvent was removed under vacuum, and

the residue was puriﬁed by silica gel chromatography, eluting with 1%

ethyl acetate in hexane to give product 44 as an oil: 105 mg (56%

C₃₂-Mycoketide: (4S,8S,12S,16S,20S)-4,8,12,16,20-Pentam-

ethyl-1-heptacosanol. A. Method A (Product 83% Stereopurity):

From 1-Benzoxy-(4R,8S,12S,16S,20S)-4,8,12,16,20-pentamethyl-5-

(E/Z)-5-heptacosene (26). A suspension of 10% Pt on carbon (48

mg, 0.025 mmol) in a solvent mixture of benzene/ethanol (1:1, v/v)

(4 mL) was pretreated with hydrogen by 5 vacuum-hydrogen cycles.

Under H₂, a solution of 26 (≤93% stereopurity, 136 mg, 0.245 mmol)

in the same solvent mixture of benzene/ethanol (1:1, v/v) (1.0 mL)

was slowly added. After the combined mixture was stirred under a

hydrogen balloon overnight, the catalyst was ﬁltered oﬀ, and the

solvent was removed. The resulting residue was dissolved in ethyl

acetate (5 mL), and 10% Pd on carbon (65 mg, 0.061 mmol) was

added. The resulting suspension was saturated with hydrogen by 5

vacuum-hydrogen cycles. After stirring overnight under hydrogen

atmosphere, TLC showed reaction was complete. The catalyst was

ﬁltered oﬀ, and the solvent was removed. The residue was puriﬁed by

silica gel chromatography, eluting with 10% ethyl acetate in hexane to

give C₃₂-mycoketide (83% stereopurity) as an oil:¹²83 mg, (73%

yield).

B. Methods B and C (Product up to 96% Stereopurity): From 1-

Benzoxy-(4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethyl-heptaco-

sane (37). 10% Pd on carbon (57 mg, 54 μmol) was added to a

solution of 37 (296 mg, 0.531 mmol) in ethyl acetate (25 mL). The

resulting suspension was saturated with hydrogen by 5 vacuum-

hydrogen cycles. After stirring overnight under a hydrogen balloon,

TLC showed reaction was complete. The catalyst was then ﬁltered oﬀ,

and the solvent was removed. The residue was puriﬁed by silica gel

chromatography, eluting with 10% ethyl acetate in hexane to give C₃₂-

mycoketide (up to 96% stereopurity) as an oil:¹²0.230 g (93% yield).

¹H NMR (CDCl₃/TMS) δ 3.60 (t, 2H, J = 6.6 Hz), 2.15 (brs, 1H),

1.67−1.47 (m, 2H), 1.45−0.98 (m, 43H), 0.92−0.82 (m, 18H); ¹³C

NMR (CDCl₃) δ 63.4, 37.6, 37.5, 37.2, 33.1, 32.94, 32.91, 32.8, 32.1,

30.5, 30.2, 29.6, 27.2, 24.6, 22.8, 19.92, 19.90, 19.8, 14.3.

1

yield). H NMR (CDCl₃/TMS) δ 7.70−7.22 (m, 15H), 5.40−5.10

(m, 2H), 4.50 (s, 2H), 3.55−3.40 (m, 4H), 2.50−1.00 (m, 29H), 1.04

(s, 9H), 0.98−0.80 (m, 15H); ¹³C NMR (CDCl₃) δ 138.9, 137.9,

137.3, 135.8, 134.3, 129.6, 128.5, 127.8, 127.7, 127.6, 127.1, 127.0,

73.0, 71.1, 69.1, 40.1, 38.1, 37.7, 37.6, 37.5, 37.4, 37.3, 37.1, 36.97,

36.95, 35.9, 34.9, 33.63, 33.59, 33.5, 33.3, 32.9, 32.8, 31.8, 27.5, 27.0,

25.1, 24.9, 24.6, 24.5, 21.5, 21.2, 19.9, 19.8, 19.6, 19.5, 17.1; HRMS

(ESI/APCl) calcd for C₄₉H₇₆O₂SiK [MK⁺] 763.5246, found 763.5236.

2 1 - B e n z o x y - 1 - t e r t - b u t y l d i p h e n y l s i l y l o x y -

(2R,6R,10R,14S,18S)-2,6,10,14,18-pentamethyl-heneicosane

(45). A. From 1-Benzoxy-21-tert-butyldiphenylsilyloxy-

(4R,8S,12R,16S,20S)-4,8,12,16,20-Pentamethyl-5-(E/Z)-13-(E/Z)-he-

neicos-5,13-diene (40). CuSO₄(7.6 mg, 0.048 mmol) was added to a

solution of 40 (346 mg, 0.478 mmol) and hydrazine (1.50 mL, 47.7

mmol) in ethanol (25 mL). After the mixture was bubbled with air and

stirred at 70 °C for 15 h, the solution was ﬁltered, and the ﬁltrate was

evaporated under vacuum. The resulting residue was extracted with

Et₂O and washed with brine. The combined organic layers were

evaporated, and the residue was puriﬁed by silica gel chromatography,

eluting with 1% ethyl acetate in hexane to give 45 as an oil: 807 mg

(96% yield).

B. From 21-Benzoxy-1-tert-butyldiphenylsilyloxy-

(2R,6S,10R,14R,18S)-2,6,10,14,18-pentamethyl-8-(E/Z)-8-heneico-

sene (44). Following to the above-described procedure, compound 44

(103 mg, 0.142 mmol) was reacted with hydrazine (0.45 mL, 14

mmol) in the presence of CuSO₄(2.3 mg, 0.014 mmol) in ethanol (10

mL) at 70 °C for 15 h to give 45 as an oil: 81 mg (78% yield).

¹H NMR (CDCl₃/TMS) δ 7.70−7.22 (m, 15H), 4.50 (s, 2H),

3.55−3.40 (m, 4H), 1.70−1.00 (m, 33H), 1.05 (s, 9H), 0.92 (d, 3H, J

= 6.8 Hz), 0.88−0.81 (m, 12H); ¹³C NMR (CDCl₃) δ 138.8, 135.8,

134.3, 129.6, 128.5, 127.72, 127.67, 127.6, 73.0, 71.0, 69.0, 37.6, 37.52,

37.49, 37.46, 35.9, 33.6, 33.5, 33.0, 32.94, 32.90, 32.8, 27.5, 27.0, 24.62,

24.59, 24.5, 19.93, 19.91, 19.8, 19.5, 17.1; HRMS (ESI/APCl) calcd

for C₄₉H₇₈O₂SiK [MK⁺] 765.5403, found 765.5414.

21-Benzoxy-(2R,6R,10R,14S,18S)-2,6,10,14,18-pentamethyl-

1-heneicosanol (46). TBAF (1.0 M in THF, 2.0 mL, 2.0 mmol) was

added to a solution of 21-benzoxy-1-tert-butyldiphenylsilyloxy-

(2R,6R,10R,14S,18S)-2,6,10,14,18-pentamethylheneicosane (45) (729

mg, 1.00 mmol) in dry THF (8 mL). After the reaction mixture was

stirred at rt overnight, the solvent was removed under vacuum, and the

residue was puriﬁed by silica gel chromatography, eluting with 10−

15% ethyl acetate in hexane to give 46 as an oil: 394 mg (81% yield).

¹H NMR (CDCl₃/TMS) δ 7.40−7.20 (m, 5H), 4.50 (s, 2H), 3.55−

Pyridinium (2,3,4,6-Tetra-O-acetyl-β-^D-mannopyranosyl)-

phosphate (48). Compound 48 was prepared according to a

procedure in the literature.¹²¹H NMR (D₂O) δ 8.67 (d, 2H, J = 5.6

Hz), 8.52 (t, 1H, J = 7.8 Hz), 7.97 (t, 2H, J = 6.8 Hz), 5.42 (d, 1H, J =

3.2 Hz), 5.35 (dd, 1H, J = 0.8, 8.8 Hz), 5.23 (dd, 1H, J = 3.2, 10.0 Hz),

5.11 (t, 1H, J = 10.0 Hz) 4.33 (dd, 1H, J = 3.6, 12.8 Hz), 4.09 (dd, 1H,

J = 1.6, 12.8 Hz), 3.96 (ddd, 1H, J = 2.0, 3.2, 10.0 Hz), 2.13 (s, 3H),

2.02 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H); ¹³C NMR (D₂O) δ 173.9,

173.3, 173.2, 172.7, 147.3, 141.2, 127.5, 93.4 (d), 71.9, 71.3, 70.1(d),

65.5, 61.9, 20.23, 20.18, 20.1.

Sodium (4S,8S,12S,16S,20S)-4,8,12,16,20-Pentamethylhep-

tacosylphosphoryl-β-^D-mannopyranoside (C₃₂-MPM). Pyridi-

nium (2,3,4,6-tetra-O-acetyl-β-^D-mannopyranosyl)-phosphate (48)

(84.0 mg, 0.163 mmol), (4S,8S,12S,16S,20S)-4,8,12,16,20-pentameth-

yl-1-heptacosanol (C₃₂-mycoketide) (38 mg, 0.081 mmol), and 2,4,6-

triisopropylbenzenesulfonyl chloride (TPSCl) (74.0 mg, 0.244 mmol)

were coevaporated with dry pyridine (2 mL) and then dry toluene (2

× 2 mL). Under argon, the resulting white foam was redissolved in dry

pyridine (2 mL), and DMAP (5.0 mg, 0.041 mmol) was added. After

stirring at rt for 48 h, the reaction was quenched with methanol (3

mL), and the mixture was stirred at rt for additional 2 h. After the

evaporation of the solvent, the resulting residue was dissolved in

chloroform and washed with water and brine. After drying over

anhydrous MgSO₄and removal of the solvent, the residue was puriﬁed

by silica gel chromatography, eluting with 10% methanol in

chloroform, to give (4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethylhep-

tacosylphosphoryl-2,3,4,6-tetra-O-acetyl-β-^D-mannopyranoside:¹²58

3.30 (m, 4H), 1.70−1.00 (m, 33H), 0.91 (d, 3H, J = 6.4 Hz), 0.88−

0.81 (m, 12H); ¹³C NMR (CDCl₃) δ 138.8, 128.4, 127.7, 127.6, 73.0,

71.0, 68.4, 37.52, 37.50, 37.44, 35.9, 33.6, 33.4, 32.91, 32.88, 32.8, 27.4,

24.6, 24.5, 19.91, 19.90, 19.8, 16.8; HRMS (ESI/APCl) calcd for

C₃₃H₆₁O₂[MH⁺] 489.4666, found 489.4670.

21-Benzoxy-(2R,6R,10R,14S,18S)-2,6,10,14,18-pentamethyl-

heneicosyl p-Toluenesulfonate (47). Under argon, p-TsCl (228

mg, 1.20 mmol) was added to a solution of 21-benzoxy-

(2R,6R,10R,14S,18S)-2,6,10,14,18-pentamethyl-1-heneicosanol (46)

(390 mg, 0.798 mmol) and DMAP (1.0 mg) in anhydrous pyridine

(5 mL) at 0 °C. After the mixture was stirred at rt overnight, water

(2.5 mL) was added, and the mixture was extracted with Et₂O (3 × 10

mL). The organic layers were combined, subsequently washed with 1

N HCl (5 mL), water (5 mL), saturated aqueous NaHCO₃(5 mL)

and brine (5 mL). The solvent was removed, and the residue was

puriﬁed by silica gel chromatography, eluting with 5% ethyl acetate in

1

mg, 83% yield. H NMR (D₂O) δ 5.48 (m, 1H), 5.42 (d, 1H, J =

7.6 Hz), 5.25−5.17 (m, 2H), 4.28 (dd, 1H, J = 4.4, 12.0 Hz), 4.16 (dd,

1H, J = 2.4, 12.4 Hz), 3.86 (m, 3H), 2.16 (s, 3H), 2.06 (s, 3H), 2.04 (s,

3H), 1.95 (s, 3H), 1.70−1.00 (m, 45H), 0.95−0.85 (m, 18H); ¹³C

NMR (CD₃OD) δ 173.0, 172.8, 172.3, 172.1, 95.7, 74.6, 73.3, 72.0,

68.5, 67.7, 64.2, 39.4, 39.33, 39.29, 39.25, 39.0, 35.1, 34.9, 34.80, 34.76,

34.7, 33.9, 31.9, 31.6, 31.4, 29.0, 26.5, 26.4, 26.3, 24.6, 21.64, 21.59,

21.5, 21.4, 21.23, 21.21, 21.16, 21.0, 15.4; ³¹P NMR (D₂O) δ −5.6.

To a solution of (4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethylhep-

tacosylphosphoryl-2,3,4,6-tetra-O-acetyl-β-^D-mannopyranoside (51

1

hexane to give 47 as an oil: 398 mg (78% yield). H NMR (CDCl₃/

TMS) δ 7.81−7.76 (m, 2H), 7.37−7.23 (m, 7H), 4.50 (s, 2H), 3.88

(dd, 1H, J = 5.6, 9.2 Hz), 3.80 (dd, 1H, J = 6.4, 9.2 Hz), 3.45 (t, 2H, J

= 6.8), 2.44 (s, 3H), 1.82−0.90 (m, 33H), 0.90−0.78 (m, 15H); ¹³C

NMR (CDCl₃) δ 144.7, 138.8, 133.3, 129.9, 128.4, 128.0, 127.7, 127.6,

75.2, 73.0, 71.0, 37.53, 37.50, 37.46, 37.44, 37.2, 33.4, 33.1, 32.92,

32.80, 32.78, 27.4, 24.58, 24.56, 24.1, 21.7, 19.9, 19.8, 16.6; HRMS

(ESI/APCl) calcd for C₄₀H₆₇O₄S [MH⁺] 643.4755, found 643.4770.

O

dx.doi.org/10.1021/jo4006602 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

mg, 0.058 mmol) in a chloroform/methanol solvent mixture (1:2.5, v/

v) (3.5 mL) was added NaOMe solution (0.5 M in MeOH, 0.20 mL,

0.10 mmol). The mixture was stirred at rt for 30 min and then diluted

with 1-butanol (15 mL). The reaction was quenched with saturated

aqueous NH₄Cl (10 mL), and the organic layer was separated, then

washed with water (3 × 10 mL), and coevaporated with toluene. The

resulting solid was washed with acetone (25 mL) and then dissolved

into a chloroform−methanol mixture (1:1, v/v) (35 mL). The solution

was ﬁltered through a pad of Celite and concentrated to give sodium

(4S,8S,12S,16S,20S)-4,8,12,16,20-pentamethylheptacosylphosphoryl-

(11) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263−2266.

(12) van Summeren, R. P.; Moody, D. B.; Feringa, B. L.; Minnaard,

A. J. J. Am. Chem. Soc. 2006, 128, 4546−4547.

(13) van Summeren, R. P.; Reijmer, S. J. W.; Feringa, B. L.;

Minnaard, A. J. Chem. Commun. 2005, 1387−1389.

(14) Des Mazery, R.; Pullez, M.; Lopez, F.; Harutyunyan, S. R.;

Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966−

9967.

(15) Buter, J.; Yeh, E. A.; Budavich, O. W.; Damodaran, K.;

Minnaard, A. J.; Curran, D. P. J. Org. Chem. 2013, 78, 4913−4918.

(16) Rylander, P. N. Hydrogenation Methods; Academic Press: New

York, 1985.

(17) Scharf, L.; Li, N.-S.; Hawk, A. J.; Garzon, D.; Zhang, T.; Fox, L.

M.; Kazen, A. R.; Shah, S.; Haddadian, E. J.; Gumperz, J. E.;

Saghatelian, A.; Faraldo-Gomez, J. D.; Meredith, S. C.; Piccirilli, J. A.;

Adams, E. J. Immunity 2010, 33, 853−862.

(18) Mercier, C.; Chabardes, P. Pure Appl. Chem. 1994, 66, 1509−

1518.

β-^D-mannopyranoside (C₃₂-MPM):¹²41 mg (100% yield). H NMR

1

(CDCl₃/CD₃OD/D₂O, 0.45:0.45:0.05) δ 5.31 (m,, 1H), 4.19−4.00

(m, 4H), 3.82 (m, 2H), 3.56 (t, 2H, J = 1.6 Hz), 1.84 (m, 2H), 1.70−

1.25 (m, 43H), 1.15−1.05 (m, 18H); ¹³C NMR (CDCl₃/CD₃OD/

D₂O, 0.45:0.45:0.05) δ 95.2, 76.6, 72.9, 70.9, 66.5, 66.2, 60.8, 37.00,

36.97, 36.93, 36.89, 36.6, 32.7, 32.4, 32.34, 32.30, 32.28, 31.5, 29.5,

29.2, 28.9, 27.9, 26.6, 24.1, 24.03, 23.97, 23.95, 22.2, 19.3, 19.2, 19.1,

18.8, 13.4; ³¹P NMR (CDCl₃/CD₃OD/D₂O, 0.45:0.45:0.05, v/v/v) δ

−1.4; MS (API-ES) calcd for C₃₈H₇₉O₉P⁻(M − Na⁺) 707.5, found

707.4.

(19) Dowd, P.; Hershline, R.; Ham, S. W.; Naganathan, S. Nat. Prod.

Rep. 1994, 11, 251−264.

(20) Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids: Vol. 2, Di-

and Higher terpenoids; Chapman and Hall: London, 1991.

(21) Moreira, J. A.; Correa, A. G. Tetrahedron: Asymmetry 2003, 14,

3787−3795.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra for all new compounds. This material

is available free of charge via the Internet at http://pubs.acs.org.

(22) Mori, K.; Harada, H.; Zagatti, P.; Cork, A.; Hall, D. R. Liebigs

Ann. Chem. 1991, 259−267.

(23) Poppe, L.; Novak, L.; Devenyi, J.; Szantay, C. Tetrahedron Lett.

1991, 32, 2643−2646.

(24) Yadav, J. S.; Gayathri, K. U.; Thrimurtulu, N.; Prasad, A. R.

Tetrahedron 2009, 65, 3536−3544.

(25) Kameda, Y.; Nagano, H. Tetrahedron 2006, 62, 9751−9757.

(26) Sankaranarayanan, S.; Sharma, A.; Chattopadhyay, S. Tetrahe-

dron: Asymmetry 2002, 13, 1373−1378.

AUTHOR INFORMATION

Corresponding Author

*E-mail: nli@uchicago.edu; jpicciri@uchicago.edu.

■

Present Address

^§Division of Biology, California Institute of Technology,

Pasadena, CA 91125.

(27) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 2000, 1307−1312.

(28) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2175−2182.

(29) Sivaraman, D.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70,

9447−9462.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

(30) Eguchi, T.; Arakawa, K.; Terachi, T.; Kakinuma, K. J. Org. Chem.

1997, 62, 1924−1933.

We thank A. Hernandez, N. Suslov, and N. Tuttle for helpful

discussions and critical comments on the manuscript. We thank

Professor Dennis Curran for sharing his manuscrip¹⁵prior to

publication.

(31) Heathcock, C. H.; Finkelstein, B. L.; Aoki, T.; Poulter, C. D.

Science (Washington, DC, U. S.) 1985, 229, 862−864.

(32) Heathcock, C. H.; Finkelstein, B. L.; Jarvi, E. T.; Radel, P. A.;

Hadley, C. R. J. Org. Chem. 1988, 53, 1922−1942.

(33) Koga, Y.; Morii, H. Biosci. Biotechnol. Biochem. 2005, 69, 2019−

2034.

REFERENCES

■

941.

(1) Barral, D. C.; Brenner, M. B. Nat. Rev. Immunol. 2007, 7, 929−

(34) Ulrih, N. P.; Gmajner, D.; Raspor, P. Appl. Microbiol. Biotechnol.

2009, 84, 249−260.

(35) Zhang, D.; Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1270−

1277.

(36) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett

1998, 26−28.

(2) Moody, D. B.; Zajonc, D. M.; Wilson, I. A. Nat. Rev. Immunol.

2005, 5, 387−399.

(3) Zeng, Z.; Castano, A. R.; Segelke, B. W.; Stura, E. A.; Peterson, P.

A.; Wilson, I. A. Science 1997, 277, 339−345.

(4) Gadola, S. D.; Zaccai, N. R.; Harlos, K.; Shepherd, D.; Castro-

Palomino, J. C.; Ritter, G.; Schmidt, R. R.; Jones, E. Y.; Cerundolo, V.

Nat. Immunol. 2002, 3, 721−726.

(37) Blakemore, P. R. J. Chem. Soc. Perkin Trans. 1 2002, 2563−2585.

(38) Nicolaou, K. C.; Schlawe, D.; Kim, D. W.; Longbottom, D. A.;

de Noronha, R. G.; Lizos, D. E.; Manam, R. R.; Faulkner, D. J.

Chem.Eur. J. 2005, 11, 6197−6211.

(5) Koch, M.; Stronge, V. S.; Shepherd, D.; Gadola, S. D.; Mathew,

B.; Ritter, G.; Fersht, A. R.; Besra, G. S.; Schmidt, R. R.; Jones, E. Y.;

Cerundolo, V. Nat. Immunol. 2005, 6, 819−826.

(39) Horita, K.; Nagasawa, M.; Sakurai, Y.; Yonemitsu, O. Chem.

Pharm. Bull. 1998, 46, 1199−1216.

(6) Zajonc, D. M.; Elsliger, M. A.; Teyton, L.; Wilson, I. A. Nat.

Immunol. 2003, 4, 808−815.

(40) KeylingBilger, F.; Schmitt, G.; Beck, A.; Luu, B. Tetrahedron

1996, 52, 14891−14904.

(7) Calabi, F.; Milstein, C. Nature 1986, 323, 540−543.

(8) Moody, D. B.; Ulrichs, T.; Muhlecker, W.; Young, D. C.; Gurcha,

S. S.; Grant, E.; Rosat, J.-P.; Brenner, M. B.; Costello, C. E.; Besra, G.

S.; Porcelli, S. A. Nature 2000, 404, 884−888.

(41) Kabalka, G. W.; Li, N.-S.; Pace, R. D. Synth. Commun. 1995, 25,

2135−2143.

(42) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365−

366.

(9) Matsunaga, I.; Bhatt, A.; Young, D. C.; Cheng, T.-Y.; Eyles, S. J.;

Besra, G. S.; Briken, V.; Porcelli, S. A.; Costello, C. E.; Jacobs, W. R.,

Jr.; Moody, D. B. J. Exp. Med. 2004, 200, 1559−1569.

(10) de Jong, A.; Arce, E. C.; Cheng, T. Y.; van Summeren, R. P.;

Feringa, B. L.; Dudkin, V.; Crich, D.; Matsunaga, I.; Minnaard, A. J.;

Moody, D. B. Chem. Biol. 2007, 14, 1232−1242.

(43) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70,

9447−9462.

(44) For the oxidation, avoid long reaction times or the use of a large

excess of Dess−Martin periodinane, since the aldehyde 17 could be

further oxidized to the corresponding carboxylic acid.

P

dx.doi.org/10.1021/jo4006602 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(45) Chan, K. K.; Cohen, N.; Denoble, J. P.; Specian, A. C.; Saucy, G.

J. Org. Chem. 1976, 41, 3497−3505.

(46) Schwartz, B. D.; Hayes, P. Y.; Kitching, W.; De Voss, J. J. J. Org.

Chem. 2005, 70, 3054−3065.

(47) Miller, C. E. J. Chem. Educ. 1965, 42, 254−259.

(48) Pasto, D. J.; Tayler, R. T. Org. React. 1991, 40, 91−155.

(49) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.

Chem. Soc., Chem. Commun. 1987, 1625−1627.

(50) Sprott, G. D.; Yeung, A.; Dicaire, C. J.; Yu, S. H.; Whitfield, D.

M. Archaea 2012, 2012, 513231.

(51) Whitfield, D. M.; Yu, S. H.; Dicaire, C. J.; Sprott, G. D.

Carbohydr. Res. 2010, 345, 214−229.

(52) Dicaire, C. J.; Yu, S. H.; Whitfield, D. M.; Sprott, G. D. J.

Liposome Res. 2010, 20, 304−314.

(53) Benvegnu, T.; Lemiegre, L.; Cammas-Marion, S. Recent Pat.

Drug Delivery Formulation 2009, 3, 206−220.

(54) Whitfield, D. M.; Eichler, E. E.; Sprott, G. D. Carbohydr. Res.

2008, 343, 2349−2360.

(55) Sprott, G. D.; Dicaire, C. J.; Cote, J. P.; Whitfield, D. M.

Glycobiology 2008, 18, 559−565.

(56) Krishnan, L.; Sprott, G. D. Vaccine 2008, 26, 2043−2055.

(57) Sprott, G. D.; Patel, G. B.; Krishnan, L. Methods Enzymol. 2003,

373, 155−172.

(58) Krishnan, L.; Sad, S.; Patel, G. B.; Sprott, G. D. Cancer Res.

2003, 63, 2526−2534.

(59) Tan, Z.; Negishi, E. I. Angew. Chem., Int. Ed. 2004, 43, 2911−

2914.

(60) Chandrasekhar, S.; Yaragorla, S. R.; Sreelakshmi, L.; Reddy, C.

R. Tetrahedron 2008, 64, 5174−5183.

(61) Murakami, N.; Wang, W. Q.; Aoki, M.; Tsutsui, Y.; Higuchi, K.;

Aoki, S.; Kobayashi, M. Tetrahedron Lett. 1997, 38, 5533−5536.

(62) Rao, A. V. R.; Desibhatla, V. Tetrahedron Lett. 1993, 34, 7111−

7114.

Q

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Highly stereocontrolled total synthesis of β-d-mannosyl phosphomycoketide: A natural product from mycobacterium tuberculosis

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