An efficient asymmetric route to tertiary carbinols: Synthesis of (R)-mevalonolactone

Article abstract of DOI:10.1055/s-2007-965956

An efficient strategy for the asymmetric construction of tertiary carbinols has been devised using cyclohexylideneglyceraldehyde as a chiral template. This involves (a) addition of a Grignard reagent (R¹MgX) to cyclohexylideneglyceraldehyde, fo

Full text of DOI:10.1055/s-2007-965956

1082
PAPER
An Efficient Asymmetric Route to Tertiary Carbinols: Synthesis of
(R)-Mevalonolactone
Synthesis of
(
R
.
)-Mevalono
Rlactone oy, A. Sharma, B. Dhotare, P. Vichare, A. Chattopadhyay, S. Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Fax +91(22)5505151; E-mail: schatt@barc.gov.in
Received 5 December 2006; revised 22 January 2007
and alkynols. However, the reagent-controlled strategies,
as well as methodologies wherein the substrates contain
temporarily incorporated chiral segments require suitable
chiral auxiliaries or promoters. While the design and syn-
Abstract: An efficient strategy for the asymmetric construction of
tertiary carbinols has been devised using cyclohexylideneglyceral-
dehyde as a chiral template. This involves (a) addition of a Grignard
reagent (R1MgX) to cyclohexylideneglyceraldehyde, followed by
oxidation with pyridinium chlorochromate to give the alkylated ke- thesis of the required chiral auxiliary provide adequate
tone, and (b) addition of a second Grignard reagent (R2MgX) to the
previously formed ketone. For alkyl chain lengths up to that of n-
decane, in the second Grignard reagent (R2MgX) or the ketone
formed in the first reaction, the reaction proceeded with complete
diastereoselectivity; with longer chains, the selectivity dropped.
The presence of a C=C bond in the second Grignard reagent
(R2MgX) or the ketone also reduced the diastereoselectivity of the
reaction. When, with regard to chain lengths of the alkyl groups in
the Grignard reactions, R2 > R1, the reaction proceeded with syn se-
lectivity, and vice versa. In general, the C-3 epimers of the target
tertiary carbinols could be prepared easily by altering the sequence
of the addition of the Grignard reagents (R1MgX and R2MgX) to
cyclohexylideneglyceraldehyde. This strategy, using inexpensive
chemicals, was applied in the simple enantiomeric synthesis of (R)-
mevalonolactone.
challenges,8 the efforts are often very taxing, and at times
frustrating. Further, syntheses of the sterically robust
chiral auxiliaries may require several steps, and involve
expensive reagents.4b In comparison, the substrate-con-
trolled strategy is sporadically employed for the synthesis
of the designated chiral moiety. Some recent
publications9a–c in this regard were primarily aimed at syn-
thesizing specific target molecules. In one of these, glyc-
eraldehyde acetonide was used,9a and only a single
example of allylation was mentioned, while other
reports9b,c were on the use of a tartrate ester as the chiral
template.
It was envisaged that a systematic investigation on the ad-
dition of organometallic reagents to an easily amenable
ketone template from the natural chiral pool might pro-
vide a general asymmetric route for the tertiary alcohols.
Further, if the chiral template is functionally rich, it would
Key words: asymmetric synthesis, chiral pool, Grignard reaction,
tertiary alcohols
Chiral compounds containing a tertiary hydroxy function assist in subsequent organic transformations. However,
are abundant in nature, and many of these show impres- this requires that the starting material is inexpensive and
sive biological activities. Amongst these, the tertiary hy- preferably available in its enantiomeric forms, and the
droxy acids and their derivatives are highly important adopted method is highly diastereo- or enantioselective
intermediates in the asymmetric synthesis of a variety of with excellent yields to offer a practical and cost-effective
medicinal agents1 and natural products.2a–e Some of the process. With this philosophy, we have developed an
tertiary carbinol-containing compounds of contemporary asymmetric synthesis of the acid component of oxybuty-
interest include the cytotoxic polyketide amphidinolide nin.9d In this paper, we extended the approach to develop
B,3a the muscarinic receptor antagonist oxybutynin,3b the a simple, efficient and economic general route for an
reverse transcriptase inhibitor taurospongin A,3c and vari- asymmetric synthesis of tertiary alcohols, and the results
ous immunoregulating agents.3d
of the investigations are presented herein.
Given the medicinal importance of these compounds, and Earlier we found that addition of Grignard reagents to the
the associated challenge in their synthesis, considerable easily accessible cyclohexylideneglyceraldehyde (1)
efforts have been devoted for the efficient construction of (Scheme 1) furnishes the diastereomeric alkanetriol de-
the chiral tertiary carbinol moiety.4 In general, these meth- rivatives, albeit in moderate to good stereoselectivity.10
ods involve enantioselective addition of nucleophiles to a The presence of the cyclohexylidene group ensured easy
suitable ketone in the presence of a chiral auxiliary separation of the resultant epimeric carbinols by normal
present in the substrate or the reagent.5 To this end, exten- column chromatography. In contrast, with isopropyli-
sive work has been carried out on the addition of organo- deneglyceraldehyde, separation of the diastereomers re-
lithium,6 organomagnesium,7a,b organozinc,7c and organo- quires their prior protection with a suitable group. These
indium7d reagents to ketones to furnish tertiary alkanols alkanetriols are versatile synthons, as exemplified by their
conversion into various bioactive compounds.11 It was en-
visaged that extension of a similar strategy with a suitable
ketone derived from 1 might be an efficient alternative for
the synthesis of chiral tertiary hydroxy compounds. The
SYNTHESIS 2007, No. 7, pp 1082–1090
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965956; Art ID: Z25406SS
x
x
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x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (R)-Mevalonolactone
1083
method would provide access to functionally rich tertiary
carbinols that can be processed into different target com-
pounds. On the basis of our previous experience, we were
tempted to pursue this protocol with the hope of good
enantioselectivity, and easy separation of the tertiary
carbinol epimers because of the bulky cyclohexyl group in
the products. Herein, we report the results of our studies
and its application to an enantiomeric synthesis of (R)-
mevalonolactone.
Table 1 Substituent Group Definitions of Compounds 2–5
Compound
2a, 3a
2b, 3b
2c, 3c
2d, 3d
2e, 3e
2f, 3f
R1
R2
Me
–
Et
–
n-Bu
–
(CH2)9Me
–
For the designated transformation leading to the asym-
metric synthesis of tertiary carbinols (Scheme 1, Table 1),
we selected a series of ketones 3a–g, and subjected them
to reactions with different Grignard reagents R2MgX.
With respect to the R2MgX used, the chosen substrate ke-
tones can be categorized into two types. Ketones 3a,b
with small alkyl groups (R1 = Me, Et, respectively) were
subjected to reactions with R2MgX containing longer
alkyl groups (R2 > R1). On the other hand, ketones 3c–g
containing larger alkyl groups [R1 = n-Bu, (CH2)9Me,
(CH2)11Me, All, (CH2)2CH=CH2, respectively] were re-
acted with methylmagnesium iodide (R1 > R2). Given that
the majority of the bioactive tertiary carbinols contains
methyl as one of the alkyl groups at the asymmetric cen-
tre, we primarily aimed at synthesis of the same structural
skeleton. For carrying out the studies, the required ketones
3a–g were conveniently prepared by reaction of aldehyde
1 with a suitable Grignard reagent R1MgX; this gave the
corresponding alcohols 2a–g as diastereomeric mixtures,
and subsequent oxidation with pyridinium chlorochro-
mate gave ketones 3a–g (Scheme 1, Table 1).
(CH2)11Me
–
All
–
2g, 3g
4a, 5a
4b, 5b
4c, 5c
4d, 5d
4e, 5e
4f, 5f
(CH2)2CH=CH2
–
Me
Me
Me
Me
Me
Me
Et
n-Bu
(CH2)5Me
(CH2)9Me
(CH2)11Me
All
(CH2)2CH=CH2
(CH2)9Me
4g, 5g
was more efficient, furnishing 4e and 5e (4e/5e, 15:85) in
76% combined yield (Table 2, entry 13). Carda et al.9a re-
ported that allylation of a glyceraldehyde-derived ketone
proceeded with 3:1 syn selectivity with allyllithium and
allylmagnesium reagents, which was improved to 4.5:1
under Barbier conditions using indium powder. In the
light of those results, the predominant anti selectivity ob-
served in the zinc-mediated allylation of 3a is significant.
However, our result on the addition of allylmagnesium
bromide to 3a was similar to that reported previously,9a al-
though the syn selectivity was only marginal in our case.
Thus, for R2MgX with R2 = (CH2)11Me or longer chain
length, and/or containing a C=C bond, the diastereoselec-
tivity was reduced. True to our expectation, the diastereo-
mers 4d–f and 5d–f (Table 2, entries 4–6) could be
separated by chromatography. To see the generality of the
above stereochemical trend in the reaction, ketone 3b was
reacted with n-decylmagnesium bromide (Table 2, entry
7). Like 3a, ethyl ketone 3b also produced a single diaste-
reomer, in this case 4g. These results confirmed that for
R2MgX with R2 up to (CH2)9Me in size, the reaction pro-
ceeds with absolute stereocontrol.
Tertiary carbinols 4 and 5 were prepared first by the reac-
tions between ketone 3a and R2MgX [R2 = n-Bu,
(CH2)5Me, (CH2)9Me, (CH2)11Me, All, (CH2)2CH=CH2],
prepared from the corresponding alkyl bromides; this
gave the corresponding alcohols 4 and 5 in excellent
yields (Scheme 1, Table 2). With R2MgX up to
R2 = (CH2)9Me, the reaction proceeded with exclusive
enantioselectivity, furnishing 4a–c as a single diastereo-
mer in each case (Table 2, entries 1–3). However, the re-
action with R2MgX containing the longer-chain alkyl
group n-dodecyl (Table 2, entry 4) gave the less polar
product 4d as the major diastereomer, along with the more
polar epimer 5d (4d/5d, 68:32). A similar trend was also
noticed with but-3-enylmagnesium bromide, which fur-
nished the less polar 4f and more polar 5f epimers in a 9:1
ratio (Table 2, entry 6). With allylmagnesium bromide,
however, the diastereoselectivity was poor, with isomers
4e and 5e obtained in a 57:43 ratio (Table 2, entry 5). On
the other hand, allylation of 3a by Luche’s procedure12
O
O
O
O
O
i
ii
iii
+
R2
R1
O
R1
OH
O
R1
O
R2
R1
O
O
CHO
HO
HO
O
1
2a–g
3a–g
4a–g
5a–g
Scheme 1 Reagents and conditions: (i) R1MgX, THF or Et2O; (ii) PCC, NaOAc, CH2Cl2; (iii) R2MgX, THF or Et2O.
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

1084
S. Roy et al.
PAPER
In principle, reversing the sequence of the addition of the The tertiary carbinols synthesized above are potentially
alkyl groups to 1 would result in the synthesis of the iso- important synthons for the synthesis of different bioactive
mers with opposite stereochemistry at C-3, provided the compounds. For example, by our own methodology,11b
Cahn–Ingold–Prelog (CIP) priority sequence of the alkyl they can be converted into tertiary amino alcohols, which
groups remains the same. Hence, it was of interest to in- are potent immunomodulators. As a first application of
vestigate if the above method could also be used for the our methodology in natural product synthesis, the six-
synthesis of the other (lower) diastereomers. For this, the membered lactone mevalonolactone (11) was considered
product profiles of the reactions between methylmagne- a suitable target (Scheme 2). The synthesis also helped in
sium iodide and ketones 3c–g were assessed (Table 2, en- ascertaining the absolute configuration of the tertiary
tries 7–12). All the reactions followed the expected carbinol centre generated in the starting material 5e.
stereochemical trend, providing the more polar epimers
either exclusively or predominantly, depending on the
(R)-(–)-Mevalonic acid or its lactone form 11 has attained
profound significance in cellular biochemistry,13a–d espe-
alkyl chain length in 3c–g. For example, the reactions
cially as an important precursor for lipids, steroidal hor-
mones, bile acids, ubiquinones, dolichols, and other
with 3c and 3d [R1 £ (CH2)9Me] furnished 5a and 5c as the
single product in each case (Table 2, entries 8, 9). In view
pentanoid compounds.13e Availability of its enantiomers
of their higher polarity compared to the epimeric counter-
is crucial in studies addressed to issues concerning cellu-
parts 4a and 4c, these were assigned the structures 5a and
5c. Likewise, the reactions of methylmagnesium iodide
with the other ketones 3e–g [containing an (CH2)11Me or
C=C bond] led to diastereomers 4d–f and 5d–f (Table 2,
entries 10–12). However, in these cases, the lower iso-
mers 5d–f were the predominant products. The combined
results are summarized in Table 2. Earlier, we observed
that the anti isomers of the secondary alcohols 3a–g are
more polar than their respective syn counterparts.10,11 On
the basis of these observations, the configurations of
4a–g and 5a–g were assigned empirically. These were
further confirmed when one of the compounds, 5e, was
converted into a known target compound. In addition, the
13C NMR resonances of the respective diastereomers
showed a definite trend, as discussed below.
lar functions ranging from cholesterol homeostasis,13a to
cell proliferation promoted by enzymes such as ras pro-
tein.13b–d In view of these, several asymmetric syntheses
of 11 have been devised, using Sharpless epoxidation,14a,b
chiral sulfoxides14c and 1,3-oxathianes,14d chiral pool ma-
terials,14e–i and enzymatic routes.14j–l
For the synthesis reported here, alcohol 5e was benzylated
to 6, which on acidic hydrolysis furnished the diol 7
(Scheme 2). Selective monobenzoylation of its primary
hydroxyl group gave 8 in good yield. Its mesylation and
subsequent reduction with lithium aluminum hydride af-
forded 9. Oxidative ozonolysis of its C=C bond15 directly
gave the d-lactone 10, which was converted into the target
compound 11 by hydrogenolysis (Scheme 2). Compari-
Table 2 Product Profiles of the Reactions of Ketones 3a–g with Grignard Reagents R2MgX
Entry
1
Ketone 3
3a
R1
R2
Products 4 + 5
4a + 5a
4b + 5b
4c + 5c
4d + 5d
4e + 5e
4f + 5f
Yielda (%)
Ratiob 4/5
100:0
100:0
100:0
68:32
57:43
90:10
100:0
0:100
0:100
10:90
22:78
10:90
15:85
Me
n-Bu
91
92
91
90
72
86
87
88
90
89
81
88
76
2
3a
Me
(CH2)5Me
(CH2)9Me
(CH2)11Me
All
3
3a
Me
4
3a
Me
5
3a
Me
6
3a
Me
(CH2)2CH=CH2
(CH2)9Me
Me
7
3b
Et
4g + 5g
4a + 5a
4c + 5c
4d + 5d
4e + 5e
4f + 5f
8
3c
n-Bu
9
3d
(CH2)9Me
(CH2)11Me
All
Me
10
11
12
13
3e
Me
3f
Me
3g
(CH2)2CH=CH2
Me
Me
3a
Allc
4e + 5e
a Yields of products 4 and 5 combined.
b Ratios based on isolated yields of the respective diastereomers.
c For this reaction, allyl bromide and zinc were used.
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Mevalonolactone
1085
OH
OH
iii
iv
O
ii
BzO
HO
O
BnO
Me
BnO
Me
RO
Me
7
8
5e R = H
R = Bn
i
6
OBn
OH
v
vi
HO
BnO
Me
O
O
O
O
9
10
11
Scheme 2 Reagents and conditions: (i) NaH, BnBr, THF, heat; (ii) aq TFA, CH2Cl2; (iii) BzCl, Et3N, CH2Cl2; (iv) MsCl, Et3N, CH2Cl2, then
LAH, THF, heat; (v) O3, CH2Cl2, aq NaOH/MeOH, –78 °C; (vi) H2, 10% Pd/C, EtOH.
son of the optical rotation of compound 11 with the report- our protocol using an easily available chiral template 1
ed value14k revealed the synthesized compound to possess was remarkably high. We routinely synthesize the tem-
the R configuration. Given that the conversion of 5e into plate 1 on a ca. 340-gram scale from D-mannitol in two
11 changed the CIP priority sequence of the adjoining steps. In consideration of these, our method appears to be
groups, compound 5e was assigned the S configuration.
superior.
By the synthesis of 11, the configurations of 4 and 5 could
be assigned. The structure of 11, obtained from 5e, con-
firmed that for the same diastereomeric pair, the more po-
lar isomers 5a–f are the anti products possessing S
configuration at the C-3 position, and vice versa. This is
in accordance with our observations11 for the secondary
carbinols 2a–g. With most of the substrates, we obtained
both the products either by serendipity (4d/5d and 4f/5f)
The IR spectra were recorded as thin films on a JASCO Model A-
1
202 FT-IR spectrophotometer. The H (200 MHz) and 13C (50
MHz) NMR spectra were recorded on a Bruker AC-200 spectrom-
eter. Optical rotations were recorded on a JASCO DIP-360 digital
polarimeter. The general experimental details are as described in
our previous publications.16 All anhydrous reactions were carried
out under an argon atmosphere in freshly dried solvents. The organ-
ic extracts were dried over anhyd Na2SO4. Microanalysis was car-
or by synthetic plan (4a/5a and 4c/5c) following a similar ried out on a Carlo Erba Elemental Analyzer model 1106.
polarity trend. In analogy with 4e/5e, these were assigned
the respective structures. Analyses of their 13C NMR spec-
tra revealed that the most downfield oxycarbon resonanc-
Carbinol Epimers 2a–g; General Procedure
Compound 1 (2.50 g, 0.015 mol) in THF or Et2O (25 mL) was added
to a well-stirred suspension of R1MgX [prepared from Mg (1.73 g,
es of the less polar isomers (4a,c,d) appear at d ~ 79–80,
while the same appear at d ~ 80–81 for the corresponding
more polar isomers (5a,c,d). Given that the reaction prod-
ucts 4b and 4g also showed the oxycarbon resonances at
d = 80.0 and 79.3 respectively, these were assigned the
syn configuration.
0.072 mol) and R1X (0.06 mol)] in THF or Et2O (for 2a, 2b, 2f) (80
mL), and the mixture was stirred until the reaction was completed
(by TLC; ca. 4 h). The reaction was quenched with 10% aq NH4Cl
(3 mL), and the mixture was filtered and concentrated in vacuo. The
residue was dissolved in Et2O (40 mL), and the organic layer was
washed with H2O (2 × 10 mL) and brine (1 × 5 mL), and dried. Sol-
vent removal in vacuo and column chromatography (100–200 mesh
silica gel, EtOAc–hexanes, 0:100 to 15:85) of the residue afforded
Thus, a highly enantiocontrolled general route for the syn-
thesis of tertiary alcohols has been developed. The meth- the respective alcohols 2a–g. Alkyl bromides were used to make the
Grignard reagents R1MgX in all cases, except for 2a where MeI was
used.
od is operationally simple and uses inexpensive chemicals
to meet the criteria of a practical method that is amenable
to scale-up. It was found that up to an alkyl chain length
of (CH2)9Me in the Grignard reagent or the ketone, the re-
action proceeded to furnish the respective tertiary
carbinols as a single diastereomer, beyond which the se-
lectivity dropped marginally. Also, the presence of a C=C
bond in the substrate or the Grignard reagent reduced the
diastereoselectivity of the reaction. The method can also
be used for the synthesis of the other epimers of the tertia-
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)butan-3-ol (2a)10
Yield: 78%; colourless oil; [a]D22 +2.4 (c 1.21, CHCl3).
IR (film): 3380, 1478 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.12 (d, J = 6.6 Hz, 3 H), 1.23–
1.39 (m, 4 H), 1.57–1.61 (m, 6 H), 2.05 (br, 1 H), 3.62–3.68 (m, 1
H), 3.84–4.03 (m, 3 H).
13C NMR (CDCl3, 50 MHz): d = 18.4, 18.5, 23.5, 23.7, 24.9, 34.5,
34.6, 35.9, 36.1, 64.6, 65.4, 67.0, 68.6, 78.9, 79.8, 109.3, 109.8.
ry alcohols, by a switch of the sequence of the Grignard
addition or by use of the easily accessible (S)-1 as the
chiral template. While the work was in progress, addition
of Grignard reagents to some tartrate-derived ketones has
been reported.9b,c As observed in the present study, the tar-
trate-derived ketones also predominantly furnished the
Cram products, albeit with modest diastereoselectivity in
most of the cases. In comparison, the stereoselectivity of
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)pentan-3-ol (2b)16a
Yield: 90%; colourless oil; [a]D22 +8.31 (c 1.14, CHCl3).
IR (film): 3443, 1089 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.97 (t, J = 7.4 Hz, 3 H), 1.36–1.42
(m, 4 H), 1.46–60 (m, 8 H), 2.22 (br, 1 H), 3.34–3.43 (m, 1 H), 3.69–
3.74 (m, 1 H), 3.91–4.02 (m, 2 H).
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

1086
S. Roy et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 10.0, 23.8, 24.0, 25.1, 26.6, 34.9,
36.3, 65.4, 65.8, 73.7, 78.5, 78.9, 109.5, 109.8.
phy of the residue (silica gel, EtOAc–hexane, 0:100 to 10:90) fur-
nished the pure ketones 3a–g.
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)heptan-3-ol (2c)16a
Yield: 88%; colourless oil; [a]D22 +6.52 (c 1.38, CHCl3).
IR (film): 3452, 1101 cm–1.
(2R)-1,2-(Cyclohexylidenedioxy)butan-3-one (3a)
Yield: 86%; colourless oil; [a]D22 +32.02 (c 1.62, CHCl3).
IR (film): 1730 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.85 (t, J = 6.4 Hz, 3 H), 1.31–1.33
(m, 6 H), 1.53–1.56 (m, 10 H), 2.40 (br, 1 H), 3.38–3.44 and 3.65–
3.69 (2 m, 1 H), 3.82–3.97 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 14.8, 22.5, 23.6, 23.8, 25.0, 27.6,
27.8, 32.2, 33.2, 34.7, 36.0, 36.3, 64.2, 64.6, 70.6, 72.2, 78.2, 78.7,
109.3, 109.7.
1H NMR (200 MHz, CDCl3): d = 1.42–1.57 (m, 10 H), 2.25 (s, 3 H),
3.93–4.00 (m, 1 H), 4.13–4.21 (m, 1 H), 4.32–4.42 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.5, 23.7, 24.8, 26.1, 34.3, 35.5,
65.8, 79.9, 111.4, 208.4.
Anal. Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.42; H,
8.58.
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)tridecan-3-ol (2d)16a
Yield: 92%; colourless oil; [a]D22 +6.18 (c 1.15, CHCl3).
IR (film): 3454, 1081 cm–1.
(2R)-1,2-(Cyclohexylidenedioxy)pentan-3-one (3b)16a
22
Yield: 72%; colourless oil; [a]D +8.41 (c 1.21, CHCl3) {Lit.16a
[a]D22 +8.24 (c 1.20, CHCl3)}.
1H NMR (200 MHz, CDCl3): d = 0.84 (t, J = 6.6 Hz, 3 H), 1.24–
1.34 [m + s (d = 1.26), 20 H], 1.53–1.62 (m, 8 H), 2.19 (br, 1 H),
3.48–3.72 (m, 1 H), 3.84–4.04 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 13.8, 22.3, 23.2, 23.5, 24.9, 25.2,
25.7, 28.8, 29.2, 30.2, 30.7, 31.1, 31.8, 32.2, 32.6, 33.1, 34.7, 35.4,
64.2, 65.3, 70.7, 71.8, 78.4, 78.7, 108.9, 109.2.
IR (film): 1718 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (t, J = 7.2 Hz, 3 H), 1.22–1.40
(m, 4 H), 1.58–1.72 (m, 6 H), 2.61 (q, J = 7.2 Hz, 2 H), 3.93 (dd,
J = 5.8, 2.8 Hz, 1 H), 4.16 (t, J = 5.8 Hz, 1 H), 4.39 (dd, J = 5.8, 3.4
Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 24.1, 26.7, 31.1, 34.1, 34.9, 35.3,
41.5, 65.9, 79.5, 111.1, 211.4.
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)pentadecan-3-ol (2e)16a
Yield: 78%; colourless oil; [a]D22 +6.93 (c 1.50, CHCl3).
IR (film): 3440, 1062 cm–1.
(2R)-1,2-(Cyclohexylidenedioxy)heptan-3-one (3c)16a
Yield: 84%; colourless oil; [a]D22 +46.85 (c 1.78, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.6 Hz, 3 H), 1.21–
1.37 [m + s (d = 1.24), 24 H], 1.55–1.60 (m, 8 H), 2.06 (br, 1 H),
3.45–3.76 (m, 1 H), 3.82–4.05 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 13.6, 22.2, 23.3, 23.5, 24.7, 25.2,
25.3, 28.9, 29.2, 30.1, 30.4, 31.2, 31.5, 31.8, 32.0, 32.6, 33.0, 34.5,
35.8, 64.3, 65.2, 70.5, 71.8, 78.1, 78.5, 108.9, 109.3.
IR (film): 1722 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 6.8 Hz, 3 H), 1.16–1.45
(m, 4 H), 1.50–1.60 (m, 10 H), 2.55 (t, J = 7.2 Hz, 2 H), 3.85–3.92
(m, 1 H), 4.11 (t, J = 7.8 Hz, 1 H), 4.32–4.38 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.7, 22.2, 23.6, 23.8, 24.8, 24.9,
34.4, 35.5, 38.0, 65.9, 79.8, 111.2, 210.7.
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)hex-5-en-3-ol (2f)16b
Yield: 88%; [a]D22 +10.07 (c 1.04, CHCl3).
IR (film): 3450, 991, 910 cm–1.
(2R)-1,2-(Cyclohexylidenedioxy)tridecan-3-one (3d)16a
Yield: 88%; colourless oil; [a]D22 +27.22 (c = 1.18, CHCl3) {Lit.16a
[a]D22 +22.5 (c 0.12, CHCl3)}.
1H NMR (200 MHz, CDCl3): d = 1.27–1.61 (m, 10 H), 2.18–2.24
(m, 2 H), 3.68–3.72 (m, 1 H), 3.82–4.15 (m, 3 H), 4.88–4.97 (m, 2
H), 5.65–5.88 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.8, 25.3, 26.6, 27.0, 32.5, 34.4,
36.7, 65.2, 73.8, 78.1, 109.8, 114.8, 138.3.
IR (film): 1715 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.24–
1.36 [m + s (d = 1.21), 20 H], 1.49–1.64 (m, 6 H), 2.61 (t, J = 7.0
Hz, 2 H), 3.89 (dd, J = 5.6, 3.5 Hz, 1 H), 4.12 (t, J = 5.6 Hz, 1 H),
4.42 (t, J = 5.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.9, 21.0, 22.2, 23.4, 23.6, 24.6,
29.1, 29.4, 29.8, 31.6, 34.6, 35.4, 39.8, 64.1, 80.1, 110.6, 208.1.
(2R,3S/R)-1,2-(Cyclohexylidenedioxy)hept-6-en-3-ol (2g)
Yield: 1.33 g (40%); colourless oil; [a]D22 +5.96 (c 1.12, CHCl3).
IR (film): 3440, 990, 910 cm–1.
(2R)-1,2-(Cyclohexylidenedioxy)pentadecan-3-one (3e)16a
22
Yield: 91%; colourless oil; [a]D +35.56 (c 1.88, CHCl3) {Lit.16a
1H NMR (200 MHz, CDCl3): d = 1.19–1.61 (m, 10 H), 1.85 (br, 1
H), 2.08–2.27 (m, 4 H), 3.47–3.53 (m, 1 H), 3.65–3.81 (m, 1 H),
3.92–4.03 (m, 2 H), 4.94–5.08 (m, 2 H), 5.71–5.89 (m, 1 H).
[a]D22 +21.52 (c 0.38, CHCl3)}.
IR (film): 1718 cm–1.
13C NMR (50 MHz, CDCl3): d = 23.7, 23.8, 23.9, 24.0, 29.6, 32.7,
1H NMR (200 MHz, CDCl3): d = 0.84 (t, J = 6.6 Hz, 3 H), 1.21–
1.39 [m + s (d = 1.23), 24 H], 1.47–1.64 (m, 6 H), 2.58 (t, J = 7.0
Hz, 2 H), 3.93 (dd, J = 5.8, 3.4 Hz, 1 H), 4.15 (t, J = 5.8 Hz, 1 H),
4.38 (t, J = 5.8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.7, 19.4, 22.3, 22.5, 23.3, 23.5,
23.8, 24.7, 25.0, 28.8, 29.0, 29.2, 29.7, 31.5, 35.3, 38.1, 65.7, 79.6,
111.0, 210.5.
34.7, 36.2, 65.6, 71.5, 78.6, 109.8, 114.9, 138.0.
Anal. Calcd for for C13H22O3: C, 68.99; H, 9.80. Found: C, 69.17;
H, 9.68.
Ketones 3a–g; General Procedure
To a cooled (0 °C) and stirred suspension of PCC (1.5 equiv) and
NaOAc (0.1 equiv) in CH2Cl2 (5 mL/mmol) was added one of alco-
hols 2a–g (1.0 equiv) in one portion. After stirring for 3 h, the reac-
tion mixture was diluted with an equal volume of Et2O and the
supernatant was passed through a pad of silica gel (5 cm × 2.5 cm).
Removal of the solvent in vacuo followed by column chromatogra-
(2R)-1,2-(Cyclohexylidenedioxy)hex-5-en-3-one (3f)16c
22
Yield: 81%; colourless oil; [a]D +37.79 (c 1.14, CHCl3) {Lit.16c
[a]D22 +37.95 (c 2.70, CHCl3)}.
IR (film): 1712 cm–1.
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Mevalonolactone
1087
1H NMR (200 MHz, CDCl3): d = 1.38–1.59 (m, 10 H), 3.31–3.44
(m, 2 H), 3.91–4.02 (m, 1 H), 4.15–4.28 (m, 1 H), 4.48 (dd, J = 7.5,
5.4 Hz, 1 H), 4.96–5.18 (m, 2 H), 5.78–5.97 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 22.8, 23.5, 26.6, 34.4, 35.2, 37.7,
65.7, 80.4, 111.4, 115.3, 137.5, 209.5.
13C NMR (50 MHz, CDCl3): d = 14.0, 21.1, 22.6, 23.4, 23.8, 23.9,
25.1, 29.8, 31.8, 34.9, 36.0, 40.3, 64.6, 71.5, 80.0, 109.6.
Anal. Calcd for C16H30O3: C, 71.07; H, 11.18. Found: C, 71.21; H,
11.29.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methyltridecan-3-ol (4c)
Colourless oil; [a]D22 +5.46 (c 1.28, CHCl3).
IR (film): 3480, 1104 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.84 (t, J = 7.2 Hz, 3 H), 1.01 (s,
3 H), 1.18–1.44 [m + s (d = 1.23), 22 H], 1.55–1.59 (m, 6 H), 2.22
(br, 1 H), 3.73–3.87 (m, 1 H), 3.90–4.10 (m, 2 H).
(2R)-1,2-(Cyclohexylidenedioxy)hept-6-en-3-one (3g)
Yield: 88%; colourless oil; [a]D22 +59.60 (c 1.45, CHCl3).
IR (film): 1722 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.23–1.65 (m, 10 H), 2.25–2.36
(m, 2 H), 2.71 (t, J = 7.8 Hz, 2 H), 3.91–3.98 (m, 1 H), 4.16 (t,
J = 8.0 Hz, 1 H), 4.31–4.43 (m, 1 H), 4.94–5.05 (m, 2 H), 5.69–5.89
(m, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.9, 21.0, 22.5, 23.3, 23.6, 23.8,
25.1, 29.2, 29.5, 30.1, 31.7, 34.8, 35.8, 40.0, 64.5, 71.2, 80.5, 109.3.
13C NMR (50 MHz, CDCl3): d = 22.7, 23.4, 26.6, 34.1, 35.0, 35.4,
37.4, 65.8, 79.6, 111.2, 114.9, 136.7, 209.9.
Anal. Calcd for C20H38O3: C, 73.57; H, 11.73. Found: C, 73.74; H,
11.62.
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.75; H,
9.15.
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-methyltridecan-3-ol (5c)
Colourless oil; [a]D22 +10.96 (c 0.292, CHCl3).
IR (film): 3474, 1105 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H), 1.04 (s,
3 H), 1.20–1.45 [m + s (d = 1.22), 22 H], 1.57–1.62 (m, 6 H), 2.18
(br s, D2O exchangeable), 3.68–3.75 (m, 2 H), 3.88–3.98 (m, 1 H).
Alcohols 4a–g and 5a–f; General Procedure
To a well-stirred soln of the appropriate Grignard reagent R2MgX
[prepared from Mg (1.8 equiv) and a suitable alkyl halide R2X (1.50
equiv)] in THF or Et2O (for MeMgI) (1.5 mL/mmol) was added
dropwise one of ketones 4a–g (1.0 equiv) in THF (1 mL/mmol). Af-
ter the mixture had stirred for 18 h at r.t., the reaction was quenched
with 10% aq NH4Cl (5 mL), and the mixture was filtered and con-
centrated in vacuo. The residue was dissolved in Et2O (40 mL), and
the organic layer was washed with H2O (2 × 10 mL) and brine
(1 × 5 mL), and dried. Solvent removal in vacuo and column chro-
matography of the residue afforded the pure alcohol(s) 4a–g and
5a–g. The yields and ratios of products 4a–g and 5a–g are summa-
rized in Table 2.
13C NMR (50 MHz, CDCl3): d = 14.2, 21.4, 22.7, 23.5, 24.0, 25.3,
29.1, 29.6, 30.1, 31.8, 36.4, 38.5, 40.2, 64.2, 71.5, 81.2, 108.9.
Anal. Calcd for C20H38O3: C, 73.57; H, 11.73. Found: C, 73.71; H,
11.58.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methylpentadecan-3-ol
(4d)
Colourless oil; [a]D22 +5.46 (c 1.28, CHCl3).
IR (film): 3462, 1108 cm–1.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methylheptan-3-ol (4a)
Colourless oil; [a]D22 +8.14 (c 1.40, CHCl3).
IR (film): 3448, 1120 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.4 Hz, 3 H), 1.01 (s,
3 H), 1.22–1.35 (m, 10 H), 1.48–1.60 (m, 6 H), 2.01 (br, 1 H), 3.78–
3.86 (m, 1 H), 3.92–3.97 (m, 2 H).
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.6 Hz, 3 H), 1.03 (s,
3 H), 1.22–1.48 [m + s (d = 1.25), 26 H], 1.58–1.62 (m, 6 H), 2.19
(br, 1 H), 3.75–3.82 (m, 1 H), 3.86–4.00 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 13.7, 20.8, 22.3, 23.1, 23.4, 24.8,
28.9, 29.3, 29.8, 31.5, 34.6, 35.6, 40.0, 64.3, 71.1, 80.2, 109.2.
13C NMR (50 MHz, CDCl3): d = 13.7, 20.8, 22.9, 23.4, 23.6, 24.8,
25.4, 34.6, 35.6, 39.7, 64.3, 71.1, 79.9, 109.2.
Anal. Calcd for C22H42O3: C, 74.52; H, 11.94. Found: C, 74.68; H,
12.02.
Anal. Calcd for C14H26O3: C, 69.38; H, 10.81. Found: C, 69.35; H,
10.69.
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-methylpentadecan-3-ol
(5d)
Colourless oil; [a]D22 +4.49 (c 1.07, CHCl3).
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-methylheptan-3-ol (5a)
Colourless oil; [a]D22 +4.80 (c 1.75, CHCl3).
IR (film): 3457, 1103 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.85 (t, J = 6.6 Hz, 3 H), 1.04 (s,
3 H), 1.22–1.33 [m + s (d = 1.24), 26 H], 1.58–1.61 (m, 6 H), 1.92
(br, 1 H), 3.77–3.82 (m, 1 H), 3.87–3.94 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.1, 22.6, 23.3, 23.8, 23.9, 24.1,
25.1, 29.3, 29.6, 30.2, 31.9, 34.9, 36.0, 37.7, 64.4, 71.7, 81.2, 109.4.
IR (film): 3423, 1104 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.02 (s,
3 H), 1.20–1.37 (m, 10 H), 1.56–1.59 (m, 6 H), 2.13 (br, 1 H), 3.75–
3.81 (m, 1 H), 3.86–3.98 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 23.3, 23.7, 23.9, 25.1, 25.4,
34.4, 35.9, 37.4, 64.4, 71.7, 81.1, 109.4.
Anal. Calcd for C22H42O3: C, 74.52; H, 11.94. Found: C, 74.41; H,
12.08.
Anal. Calcd for C14H26O3: C, 69.38; H, 10.81. Found: C, 69.53; H,
10.93.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methylhex-5-en-3-ol (4e)
Colourless oil; [a]D22 +9.03 (c 0.30, CHCl3).
IR (film): 3454, 993, 912 cm–1.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methylnonan-3-ol (4b)
Colourless oil; [a]D22 +9.47 (c = 1.41, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.06 (s, 3 H), 1.22–1.25 (m, 2 H),
1.40–1.48 (m, 2 H), 1.58–1.78 (m, 6 H), 1.99 (br, 1 H), 2.12–2.40
(m, 2 H), 3.77–3.83 (m, 1 H), 3.86–3.99 (m, 2 H), 5.06–5.14 (m, 2
H), 5.77–5.98 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.5, 23.8, 25.1, 34.5, 35.8, 44.6,
64.4, 71.2, 80.1, 109.7, 118.4, 133.5.
IR (film): 3480, 1103 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.84 (distorted t, 3 H), 1.03 (s, 3
H), 1.21–1.38 (m, 16 H), 1.48–1.60 (m, 4 H), 2.03 (br, 1 H), 3.75–
3.86 (m, 1 H), 3.89–4.12 (m, 2 H).
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

1088
S. Roy et al.
PAPER
(2R,3S)-3-(Benzyloxy)-1,2-(cyclohexylidenedioxy)-3-methyl-
Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.77; H,
9.98.
hex-5-ene (6)
To a stirred suspension of pentane-washed NaH (50% suspension in
oil; 0.934 g, 19.46 mmol) in THF (30 mL) was added 5e (4.0 g,
17.70 mmol) in THF (20 mL) at r.t. over 30 min. After the mixture
had heated at reflux for 1 h, BnBr (3.63 g, 21.24 mmol) in THF (20
mL) was added to it, and the mixture was heated at reflux for an ad-
ditional 1 h. It was brought to r.t., poured into ice-cold H2O (25 mL),
the organic layer was separated, and the aqueous phase was extract-
ed with Et2O (2 × 25 mL). The combined organic extracts were
washed with H2O (1 × 10 mL) and brine (1 × 5 mL), and dried. Sol-
vent removal in vacuo gave a residue, which was purified by col-
umn chromatography (silica gel, EtOAc–hexane, 0:100 to 10:90).
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-methylhex-5-en-3-ol (5e)
Colourless oil; [a]D22 +20.72 (c 0.40, CHCl3).
IR (film): 3451, 990, 915 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20 (s, 3 H), 1.32–1.37 (m, 4 H),
1.56–1.62 (m, 6 H), 2.00 (br, 1 H), 2.08–2.15 (m, 1 H), 2.26 (dd,
J = 14.0, 6.6 Hz, 1 H), 3.75–3.78 (m, 1 H), 3.84–4.06 (m, 2 H),
5.04–5.13 (m, 2 H), 5.74–5.95 m, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.7, 23.9, 25.1, 34.7, 35.9, 42.6,
64.4, 71.7, 80.7, 109.6, 118.7. 133.1.
Yield: 4.70 g (84%); colourless oil; [a]D22 +2.50 (c 1.12, CHCl3).
IR (film): 3060, 1584, 998, 915 cm–1.
Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found: C, 69.15; H,
9.64.
1H NMR (200 MHz, CDCl3): d = 1.22–1.41 [m + s (d = 1.28), 5 H],
1.58–1.65 (m, 8 H), 2.39–2.47 (m, 2 H), 3.95–4.19 (m, 4 H), 4.57–
4.59 (m, 1 H), 5.10–5.18 (m, 2 H), 5.86–5.98 (m, 1 H), 7.24–7.43
(m, 5 H).
13C NMR (50 MHz, CDCl3): d = 23.7, 25.1, 34.2, 35.8, 40.2, 64.4,
64.8, 76.4, 78.9, 109.5, 118.2, 127.1, 127.4, 130.8, 133.4, 140.0.
(2R,3R)-1,2-(Cyclohexylidenedioxy)-3-methylhept-6-en-3-ol
(4f)
Colourless oil; [a]D22 +4.50 (c 1.11, CHCl3).
IR (film): 3448, 988, 912 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 3 H), 1.22–1.76 (m, 12 H),
1.95 (br, 1 H), 2.11–2.19 (m, 2 H), 3.75–3.80 (m, 1 H), 3.89–3.94
(m, 2 H), 4.91–5.06 (m, 2 H), 5.72–5.92 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.1, 23.6, 23.8, 25.0, 27.8, 34.8,
35.8, 39.1, 64.5, 71.2, 80.3, 109.5, 114.2, 138.7.
Anal. Calcd for C20H28O3: C, 75.91; H, 8.92. Found: C, 75.77; H,
8.75.
(2R,3S)-3-(Benzyloxy)-3-methylhex-5-ene-1,2-diol (7)
A mixture of 6 (3.50 g, 11.08 mmol) and 90% aq TFA (15 mL) in
CH2Cl2 (30 mL) was stirred at 0 °C until 6 had disappeared (by
TLC). The mixture was extracted with CHCl3 (2 × 25 mL), and the
organic layer was washed with H2O (2 × 10 mL) and brine (1 × 5
mL), and dried. Solvent removal in vacuo followed by column chro-
matography of the residue (silica gel, MeOH–CHCl3, 0:100 to 5:95)
furnished 7.
Yield: 2.12 g (81%); colourless oil; [a]D22 +17.45 (c 1.25, CHCl3).
IR (film): 3551, 1588, 1120, 994, 914 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.32 (s, 3 H), 2.19 (br, 2 H), 2.30–
2.61 (m, 2 H), 3.66–3.81 (m, 2 H), 4.44–4.69 (m, 3 H), 5.10–5.19
(m, 2 H), 5.78–5.98 (m, 1 H), 7.26–7.44 (m, 5 H).
Anal. Calcd for C14H24O3: C, 69.96; H, 10.07. Found: C, 69.81; H,
10.18.
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-methylhept-6-en-3-ol
(5f)
Colourless oil; [a]D22 +4.20 (c 1.02, CHCl3).
IR (film): 3466, 990, 909 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.05 (s, 3 H), 1.22–1.60 (m, 12 H),
1.83 (br, 1 H), 2.07–2.18 (m, 2 H), 3.78–3.88 (m, 1 H), 3.91–3.99
(m, 2 H), 4.91–5.06 (m, 2 H), 5.71–5.91 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.8, 23.9, 25.2, 27.6, 34.9, 35.9,
36.6, 64.4, 71.7, 81.2, 109.5, 114.0, 138.6.
13C NMR (50 MHz, CDCl3): d = 23.2, 40.2, 64.1, 64.4, 76.0, 79.1,
118.2, 127.4, 130.8, 133.4, 138.7.
Anal. Calcd for C14H24O3: C, 69.96; H, 10.07. Found: C, 69.78; H,
10.21.
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.33; H,
8.38.
(2R,3S)-1,2-(Cyclohexylidenedioxy)-3-ethyltridecan-3-ol (4g)
Colourless oil; [a]D22 +3.55 (c 1.29, CHCl3).
IR (film): 3440, 1060 cm–1.
(2R,3S)-1-(Benzoyloxy)-3-(benzyloxy)-3-methylhex-5-en-2-ol
(8)
1H NMR (200 MHz, CDCl3): d = 0.85 (t, J = 7.2 Hz, 6 H), 1.24–
1.47 [m + s (d = 1.24), 24 H], 1.57–1.59 (m, 6 H), 2.08 (br, 1 H),
3.78–3.89 (m, 1 H), 3.94–4.15 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 13.9, 22.5, 23.2, 23.7, 23.8, 25.1,
26.7, 29.2, 29.5, 30.1, 31.8, 35.0, 35.9, 36.2, 64.1, 73.0, 79.3, 108.9.
To a stirred and cooled (0 °C) soln of 7 (1.0 g, 4.24 mmol) in
CH2Cl2 (15 mL) containing Et3N (0.650 mL, 4.66 mmol) was in-
jected BzCl (0.655 g, 4.66 mmol) over 20 min. The mixture was
stirred for 1.5 h at 0 °C and treated with H2O (15 mL). The organic
layer was separated and washed with H2O (1 × 10 mL) and brine
(1 × 5 mL), and dried. Solvent removal in vacuo afforded the resi-
due, which was purified by column chromatography (silica gel,
EtOAc–hexane, 0:100 to 15:85) to furnish 8.
Anal. Calcd for C21H40O3: C, 74.06; H, 11.84. Found: C, 73.91; H,
11.78.
Alternative Synthesis of 4e and 5e12
Yield: 1.08 g (75%); colourless oil; [a]D22 +44.41 (c 0.84, CHCl3).
To a mixture of 3a (1.84 g, 0.01 mol), allyl bromide (1.82 g, 0.015
mol), and Zn dust (1.30 g, 0.02 mol) in THF (40 mL) was added sat.
aq NH4Cl (2 mL) in portions. The mixture was stirred for an addi-
tional 30 min until 3a had disappeared (by TLC), and filtered. The
filtrate was extracted with EtOAc (30 mL), and the organic extract
was washed with H2O (2 × 10 mL) and brine (1 × 5 mL), and dried.
Solvent removal in vacuo and column chromatography of the resi-
due (silica gel, EtOAc–hexane, 0:100 to 20:80) afforded pure 4e
and 5e (4e/5e, 15:85); overall yield: 76%.
IR (film): 3441, 1715, 1590, 995 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 (s, 3 H), 2.04 (br, 1 H), 2.39–
2.67 (m, 2 H), 4.02–4.14 (m, 1 H), 4.38–4.69 (m, 4 H), 5.12–5.22
(m, 2 H), 5.89–5.97 (m, 1 H), 7.25–7.56 (m, 8 H), 8.05 (d, J = 7.5
Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 19.5, 39.5, 63.9, 66.6, 73.3, 78.4,
118.3, 118.5, 127.4, 128.4, 129.7, 130.0, 133.1, 133.5, 138.9, 169.3.
Anal. Calcd for C21H24O4: C, 74.09; H, 7.11. Found: C, 74.14; H,
7.25.
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Mevalonolactone
1089
(S)-3-(Benzyloxy)-3-methylhex-5-en-1-ol (9)
1H NMR (200 MHz, CDCl3): d = 1.38 (s, 3 H), 1.88–1.99 (m, 2 H),
2.50 (d, J = 17.0 Hz, 1 H), 2.66 (d, J = 17.0 Hz, 1 H), 3.51 (s, 1 H),
4.25–4.39 (m, 1 H), 4.55–4.60 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.5, 35.7, 44.5, 65.9, 68.0, 170.7.
MsCl (0.23 mL, 2.91 mmol) was added dropwise over 15 min to a
cooled (0 °C) and stirred soln of 8 (0.900 g, 2.65 mmol) and Et3N
(0.406 mL, 2.91 mmol) in CH2Cl2 (15 mL). After the mixture had
stirred for another 0.5 h at that temperature, H2O (15 mL) was add-
ed, and the mixture was extracted with CH2Cl2 (2 × 20 mL). The or-
ganic extract was washed with H2O (2 × 10 mL) and brine (1 × 5
mL), and dried. Solvent removal in vacuo afforded the residue con-
taining the crude mesylate.
References
(1) (a) Bugno, C.; Colombani, S. M.; Dapporto, P.; Garelli, G.;
Giorgi, R.; Paoli, P.; Subissi, A.; Turbanti, L. Chirality 1997,
9, 713. (b) Atkinson, E. R.; McRitchi, D. D.; Schoer, L. F.;
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IR (film): 1377, 1178, 990, 912 cm–1.
A soln of the above mesylate in THF (30 mL) was added dropwise
to a suspension of LAH (0.266 g, 7.0 mmol) in THF (30 mL) at r.t.
After the mixture had heated at reflux for 4 h, it was cooled with ice
water, and treated with sat. aq Na2SO4 (1.5–2.0 mL). The white ge-
latinous precipitate was filtered, the precipitate was washed with
Et2O, and the filtrate was concentrated in vacuo. This gave a residue
which was purified by column chromatography (silica gel, EtOAc–
hexane, 0: 100 to 15:85) to afford 9.
Yield: 0.314 g (54%); colourless oil; [a]D22 –19.79 (c 1.10, CHCl3).
IR (film): 3448, 995, 920 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33 (s, 3 H), 1.64–1.77 (m, 1 H),
1.88–2.07 (m, 1 H), 2.35–2.54 (m, 2 H), 2.88 (br, 1 H), 3.73–3.89
(m, 2 H), 4.40 and 4.62 (2 × s, 2 H), 5.10–5.17 (m, 2 H), 5.74–5.95
(m, 1 H), 7.34 (m, 5 H).
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(b) Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J. Am.
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13C NMR (50 MHz, CDCl3): d = 22.7, 39.8, 42.8, 63.6, 64.9, 78.3,
118.1, 126.8, 127.4, 128.4, 133.6, 138.6, 140.9.
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.45; H,
9.38.
(R)-3-(Benzyloxy)-3-methyl-5-hexanolide (10)
O3 was bubbled through a cooled (–78 °C) soln of 9 (0.300 g, 1.36
mmol) in CH2Cl2 (20 mL) and 2.5 M NaOH in H2O–MeOH (1:5)
(2.5 mL) until the soln turned blue (ca. 20 min). The mixture was
brought to r.t., the organic layer was separated, and the aqueous lay-
er was extracted with CHCl3 (2 × 15 mL). The combined organic
extracts were washed with H2O (1 × 10 mL) and brine (1 × 5 mL),
and dried. Solvent removal in vacuo followed by column chroma-
tography of the residue (silica gel, EtOAc–hexane, 0:100 to 20:80)
afforded 10.
Yield: 0.192 g (64%); colourless oil; [a]D22 –19.79 (c 1.10, CHCl3).
IR (film): 3034, 1734, 1603 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 3 H), 1.83–1.92 (m, 1 H),
2.02–2.08 m, 1 H), 2.48 (d, J = 17.2 Hz, 1 H), 2.75 (d, J = 17.2 Hz,
1 H), 3.85–3.91 (m, 1 H), 4.14–4.41 (m, 3 H), 7.32 (m, 5 H).
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13C NMR (50 MHz, CDCl3): d = 22.7, 39.8, 42.7, 63.9, 65.6, 72.5,
127.1, 127.3, 127.5, 128.3, 138.0, 170.0.
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.63; H,
7.55.
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(R)-3-Hydroxy-3-methyl-5-hexanolide (11)
A mixture of 10 (0.190 g, 0.86 mmol) and 10% Pd/C (0.030 g) in
EtOH (15 mL) was magnetically stirred under a slightly positive
pressure of H2 gas. After the required consumption of H2, the mix-
ture was diluted with Et2O (15 mL), and the supernatant was passed
through a 5-cm pad of silica gel. Concentration of the eluent in vac-
uo, followed by preparative TLC (silica gel, EtOAc–hexane, 15:85)
of the residue afforded pure 11.
22
Yield: 0.1 g (90%); colourless oil; [a]D –18.57 (c 1.10, CHCl3)
{Lit.14k [a]D25 –19.0 (c 2.15, CHCl3)}.
IR (film): 3450, 1672 cm–1.
(12) Petrier, C.; Luche, J. L. J. Org. Chem. 1993, 58, 910.
Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York

1090
S. Roy et al.
PAPER
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Synthesis 2007, No. 7, 1082–1090 © Thieme Stuttgart · New York