Enantioselective synthesis of (R)-incrustoporin, an antibiotic isolated from Incrustoporia carneola

Article abstract of DOI:10.1016/S0957-4166(99)00085-3

Highly enantiomerically enriched (R)-incrustoporin was enantioselectively synthesized in 43.6% overall yield starting from 4- iodotoluene. The key steps of the synthesis included the asymmetric hydrogenation of 1-(p-tolyl)-1-pentyn-3-one catalyzed by a non-racemic Ru(II) complex and the Pd-catalyzed cyclocarbonylation of so-obtained highly enantiomerically enriched 1-(p-tolyl)-1-pentyn-3-ol. This Pd-catalyzed reaction, whose stereochemical outcome was previously unknown, proceeded with retention of configuration and 2.5% or less racemization. The enantiomeric purities of (R)-1-(p-tolyl)-1-pentyn-3-ol and (R)-incrustoporin were evaluated by HPLC analysis on a Chiralcel OJ column as well as by performing the ¹H NMR spectra of these compounds in a D₂O solution which was saturated with α- or β-cyclodextrin, respectively.

Full text of DOI:10.1016/S0957-4166(99)00085-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1163–1172
Enantioselective synthesis of (R)-incrustoporin, an antibiotic
isolated from Incrustoporia carneola
Renzo Rossi,a,∗ Fabio Bellina,a Matteo Biagetti a and Luisa Manninab
aDipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
bCorso di Laurea in Scienze Ambientali, Università del Molise, Via Mazzini 8, I-86170 Isernia, Italy
Received 16 February 1999; accepted 8 March 1999
Abstract
Highly enantiomerically enriched (R)-incrustoporin was enantioselectively synthesized in 43.6% overall yield
starting from 4-iodotoluene. The key steps of the synthesis included the asymmetric hydrogenationof 1-(p-tolyl)-1-
pentyn-3-one catalyzed by a non-racemic Ru(II) complex and the Pd-catalyzed cyclocarbonylation of so-obtained
highly enantiomerically enriched 1-(p-tolyl)-1-pentyn-3-ol. This Pd-catalyzed reaction, whose stereochemical
outcome was previously unknown, proceeded with retention of configuration and 2.5% or less racemization. The
enantiomeric purities of (R)-1-(p-tolyl)-1-pentyn-3-ol and (R)-incrustoporin were evaluated by HPLC analysis on
a Chiralcel OJ column as well as by performing the 1H NMR spectra of these compounds in a D2O solution which
was saturated with α- or β-cyclodextrin, respectively. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In connection with our ongoing projects relating to the synthesis of natural and unnatural 5H-furan-
2-one derivatives,1 we recently became interested in developing a convenient and efficient synthesis
of (−)-incrustoporin [(−)-3-(p-tolyl)-5-ethyl-5H-furan-2-one] 1a, an antifungal antibiotic isolated from
the Basidiomycete Incrustoporia carneola.2 The absolute configuration of this compound has been
established as R by synthesis starting from (S)-1,2-epoxybutane and methyl p-tolylacetate.3
∗
Corresponding author. E-mail: rossi@dcci.unipi.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00085-3

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We sought a procedure for the synthesis of (R)-1a in which commercially available and inexpensive
starting materials could be used and which would be more simple and efficient than the methods
employed so far in the literature for the preparation of chiral non-racemic 3,5-disubstituted 5H-furan-
2-ones 1.4–9 We felt that a recently reported method for the synthesis of racemic compounds 1,10 which
is based on the Pd-catalyzed cyclocarbonylation of 1-alkynylcarbinols (Eq. 1), could be employed for
the preparation of highly enantiomerically enriched (R)-1a provided that a suitable chiral non-racemic
propargylic alcohol was used and the Pd-catalyzed cyclocarbonylation, whose stereochemical outcome
was unknown, occurred stereospecifically.
(1)
On the other hand, highly enantiomerically enriched propargylic alcohols such as those employed for
the synthesis of (R)-1a, i.e. 2a, can be easily obtained by asymmetric reduction of the corresponding
α,β-acetylenic ketones.11
As shown from the retrosynthetic analysis reported in Scheme 1, the chiral alcohol to be employed
in the synthesis of (R)-1a could be (R)- or (S)-2a depending on the stereochemistry of the Pd-catalyzed
cyclocarbonylation reaction. On the other hand, it must be taken into account that it has been reported that
the Pd(PPh3)4-catalyzed carbonylation of enantiomerically enriched propargylic mesylates in aqueous
THF, which affords allenic acids, occurs with inversion of configuration and 10% or less racemization.4
Scheme 1.
Herein we wish to report and comment on the results obtained in the study of the synthesis of (RS)-
1a and (R)-1a. In fact, we commenced our study by preparing (RS)-1a since its synthesis, which was
performed on the basis of a retrosynthetic analysis very similar to that shown in Scheme 1, could allow
us to probe the efficiency and selectivity of the procedure. Moreover, the availability of (RS)-1a and its
key precursor, i.e. (RS)-2a, could allow analytical procedures to be set up for evaluating the enantiomeric
purities of the corresponding non-racemic compounds as well as to test the biological activity of (RS)-1a
which is so far unknown.

R. Rossi et al. / Tetrahedron: Asymmetry 10 (1999) 1163–1172
1165
2. Results and discussion
Compound (RS)-1a was synthesized according to the reaction sequence depicted in Scheme 2. In
particular, 4-ethynyltoluene 3, which was prepared in 92% yield by reaction of 4-iodotoluene with
ethynylmagnesium bromide in THF at 0°C in the presence of 5 mol% Pd(PPh3)412, was converted into
the corresponding 1-alkynylzinc bromide by treatment with a THF solution of ethylmagnesium bromide
followed by transmetallation with a molar excess of dry ZnBr2. Reaction between this organozinc
derivative and propionyl chloride at 0°C in the presence of a catalytic amount of Pd(PPh3)4 provided
compound 5 in 81% yield. This ketone was then converted in 82% yield into the corresponding α,β-
acetylenic alcohol (RS)-2a by reaction with NaBH4 in 2-propanol at 0°C.
Scheme 2. (a) EtMgBr, THF, ∆; (b) ZnBr2, 0°C; (c) C2H5COCl (4), Pd(PPh3)4, 4 h at 0°C, 1 h at 20°C, 81%; (d) NaBH4,
2-propanol, 0°C, 82%; (e) Pd(dba)2, dppb, CO (600 psi), H2 (200 psi), CH2Cl2, 95°C, 48 h, 68%
Finally, according to a procedure for the Pd-catalyzed cyclocarbonylation of racemic 1-
alkynylcarbinols,10 a CH2Cl2 solution of (RS)-2a was treated with carbon monoxide and hydrogen in
the presence of catalytic quantities of Pd(dba)2 and 1,4-bis(diphenylphosphino)butane (dppb) for 48 h at
95°C. This reaction provided chemically pure (RS)-1a in 68% yield.
Analytical procedures for the separation of both enantiomers of (RS)-2a and (RS)-1a were then
developed. As a result, these enantiomers were found to be easily separated by HPLC on a Chiralcel
OJ column. Moreover, the enantiomers of (RS)-2a were also well differentiated by 1H NMR analysis of
this racemic alcohol in a D2O solution containing α-cyclodextrin (α-CD). This analysis showed that the
signal assigned to the H-3 proton (δ 4.605) (Fig. 1a) was shifted upfield and was resolved into two well
defined triplets of equal intensity in the presence of α-CD.
The largest signal separation (∆δ=27.0 Hz) was observed when the 1H NMR spectrum was performed
using a saturated solution of α-CD in D2O (Fig. 1b). Interestingly, either an upfield shift or an
enantiomeric resolution was also observed for the H-5 resonance of (RS)-2a. However, in this case the
1
∆δ value was 4.2 Hz. On the other hand, the enantiomers of (RS)-1a were differentiated by H NMR
analysis by perfoming the spectrum of this compound in a D2O solution containing β-cyclodextrin (β-
CD). Also in this case, the largest separation of the signals of the two enantiomeric forms was observed
when the spectrum was performed using a saturated solution of β-CD in D2O. Thus, the H-5 resonance
(δ 5.271) was shifted downfield and resolved in two partly overlapping doublets of triplets, which were
separated by 4.2 Hz. On the contrary, the doublets assigned to the H-4 proton (δ 7.909) and the H-9 and
H-13 protons (δ 7.709), respectively, were shifted upfield and each of these doublets was resolved in two
doublets which were separated by 6.6 and 3.6 Hz, respectively (Fig. 2).

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Figure 1. (a) 600.13 MHz 1H NMR spectrum of (RS)-1-(p-tolyl)-1-pentyn-3-ol in D2O. The H-3 triplet at δ 4.605 is shown. (b)
600.13 MHz 1H NMR spectrum of the same compound in a saturated solution of α-cyclodextrin in D2O. (c) 600.13 MHz 1H
22
NMR spectrum of (R)-(+)-1-(p-tolyl)-1-pentyn-3-ol, [α]D +15.91 (c 0.993, Et2O) in a saturated solution of α-cyclodextrin in
D2O
Figure 2. (a) 600.13 MHz 1H NMR spectrum of (RS)-incrustoporin in D2O. The H-4 doublet at δ 7.909 and the H-9,
1
H-13 doublet at δ 7.709 are shown. (b) 600.13 MHz H NMR spectrum of the same compound in a saturated solution of
1
25
β-cyclodextrin in D2O. (c) 600.13 MHz H NMR spectrum of (R)-(−)-incrustoporinin, [α]D −5.77 (c 3.156, CHCl3) in a
saturated solution of β-cyclodextrin in D2O
Next we turned our attention to the synthesis of enantiomerically enriched (R)-1a and, supposing
that this compound could be prepared by Pd-catalyzed cyclocarbonylation of enantiomerically enriched
(R)-2a, we first synthesized this alcohol by asymmetric reduction of compound 5 with a molar excess
of (R)-alpine-borane according to a modification13 of the general procedure described by Midland and
coworkers.11b This reaction (Scheme 3) gave ca. 87% yield of compound (+)-2a, [α]D22 +14.54 (c 1.04,
Et2O), which on the basis of HPLC analyses on a Chiralcel OJ column was estimated to be 88.6%
enantiomerically pure.
On the other hand, the much more enantiomerically enriched (+)-2a, was prepared by asymmetric
transfer hydrogenation of compound 5 according to a general procedure developed by Noyori and
coworkers.11a In particular, compound 5 was asymmetrically reduced with 2-propanol in the presence
of a Ru(II) catalyst, which was generated in situ by mixing [RuCl2(η6-p-cymene)]2, (1R,2R)-N-(p-
toluenesulfonyl)-1,2-diphenylethylene-diamine [(R,R)-Ts-DPEN] and KOH in a 1:2:5 molar ratio, res-
22
pectively. This reaction gave in 86% yield compound (+)-2a, [α]D +15.91 (c 0.993, Et2O), which on
the basis of HPLC analyses on a Chiralcel OJ column was 96.8% enantiomerically pure (Scheme 3).

R. Rossi et al. / Tetrahedron: Asymmetry 10 (1999) 1163–1172
1167
Scheme 3. (a) (i) (R)-Alpine-borane, THF, 46 h, 20°C; (ii) MeCHO; (iii) −THF, −α-pinene; (iv) ethanolamine, Et2O; (v) MPLC
on silica gel, 87%; (b) [RuCl2(η6-p-cymene]2, (R,R)-Ts-DPEN, KOH, 2-propanol, 28°C, 4 h, 86.2%; (c) Pd(dba)2, dppb, CO
(600 psi), H2 (200 psi), CH2Cl2, 95°C, 48 h, 68–69%
1
Moreover, H NMR analysis of this sample of (+)-2a in a saturated solution of α-CD in D2O allowed
us to assign to this alcohol an e.e. of ca. 99%. This value was obtained by deconvolution of the H-3
resonance of (+)-2a (Fig. 1c).
The configuration of (+)-2a was expected to be R on the basis of either the tentative mechanism
of reduction of acetylenic ketones with (R)-alpine-borane14 or the configuration of known propargylic
alcohols prepared by this method.11b,d On the other hand, this tentative configurational assignment
could be confirmed by taking into account that the asymmetric transfer hydrogenation of α,β-acetylenic
ketones by chiral Ru(II) complexes, which are obtained using (S,S)-TsDPEN as the chiral ligand, affords
propargylic alcohols of S configuration.11a
22
We were then pleased to observe that the Pd-catalyzed cyclocarbonylation of (R)-2a having [α]D
+15.91 (c 0.993, Et2O) afforded in 68% yield compound (R)-1a, which on the basis of HPLC analyses
on a Chiralcel OJ column proved to be 95.2% enantiomerically pure (Scheme 3). Unfortunately, the e.e.
1
of this compound could not be accurately evaluated by its H NMR analysis in a saturated solution of
β-CD in D2O. Nevertheless, on the basis of the area of the signals attributed to the H-4 proton (Fig. 2c),
the enantiomeric purity of this sample was estimated to be higher than 91%.
22
It was also found that the Pd-catalyzed cyclocarbonylation of (R)-2a having [α]D +14.54 (c 1.04,
Et2O) produced in 69% yield compound (R)-1a, which by HPLC analysis on a Chiralcel OJ column was
estimated to be 86.1% enantiomerically pure. Thus, this reaction occurred with retention of configuration
and 2.5% or less, of racemization.
It must be noted that these stereochemical results were not in agreement with those expected on the
basis of the mechanism suggested by Yu and Alper10 for the Pd-catalyzed cyclocarbonylation reaction
of racemic 1-alkynylcarbinols. In fact, since in this mechanism the first step of the catalytic cycle
involves insertion of Pd(0) into the C–O bond of the 1-alkynylcarbinol, which thus affects the stereogenic
center of this compound, analogous to what has been observed for the Pd-catalyzed carbonylation
of enantiomerically enriched propargylic mesylates,5 the cyclocarbonylation reaction of (R)-2a should
occur with inversion of configuration. However, our stereochemical results could be explained on the
basis of a previously reported mechanism for the Pd-catalyzed carbonylation of ethynylcarbinols in 1,2-
dimethoxyethane solution,15 in which a catalytic step involves insertion of complex 6 into the O–H bond
of ethynylcarbinols to afford complex 7.

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Nevertheless, this Pd-catalyzed reaction does not require the presence of hydrogen, which on the
contrary seems to be necessary in order to obtain 5H-furan-2-ones 1 in the Pd-catalyzed reaction
involving 1-alkynyl-carbinols.5
In conclusion, 95.2% enantiomerically pure (R)-incrustoporin (R)-1a has been enantioselectively
synthesized in 43.6% overall yield by a procedure in which 4-iodotolune was the starting material and the
key step was the Pd-catalyzed cyclocarbonylation of highly enantiomerically enriched (R)-1-(p-tolyl)-1-
pentyn-3-ol (R)-2a, which was easily available by Ru(II)-catalyzed asymmetric transfer hydrogenation of
the corresponding α,β-acetylenic ketone. It has also been shown that the Pd-catalyzed cyclocarbonylation
of a chiral non-racemic 1-alkynylcarbinol such as (R)-2a proceeds with retention of configuration, and at
least in this case, with ca. 2.5% or less, of racemization.
We are currently trying to expand the scope of the strategy, which has been used for the synthesis
of (R)-1a, to the preparation of other non-racemic naturally occurring 3,5-disubstituted 5H-furan-2-ones
which are characterized by interesting biological properties and for which the absolute configuration is
so far unknown.
3. Experimental
All reactions involving air- and water-sensitive materials were performed in flame dried glassware
under an argon atmosphere. Air- and water-sensitive solutions were transferred with hypodermic syringes
or double-ended needles. Precoated plastic silica gel sheets (Merck 60 F254) were used for TLC
analyses. GLC analyses were performed on a Dani GC 1000 instrument with a PTV injector, which
was equipped with a Dani data station 86.01. Two types of capillary columns were used: an Alltech
AT-1 bonded FSOT column (30 m×0.25 mm i.d.) and an Alltech AT-35 bonded FSOT column (30
m×0.25 mm i.d.). Purifications by MPLC were performed on a Büchi instrument, using a Bischoff
8100 differential refractometer as detector. GLC/MS analyses were performed using a Q-mass 910
spectrometer interfaced with a Perkin–Elmer 8500 gas chromatograph. HPLC analyses were performed
using a Perkin–Elmer series 410 LC pump, a 785A UV–vis detector, a 1020 Perkin–Elmer data
1
station and a Chiralcel OJ column (25 cm×4.6 mm). H and 13C NMR spectra were recorded on
a Varian Gemini 200 MHz spectrometer or a Bruker AMX 600 spectrometer using TMS or CDCl3
as an internal standard, respectively. The structural assignments were performed by a combination of
1
1
NMR techniques which included H–1H-COSY, NOESY, H–13C heteronuclear shift correlation and
1H–13C long range heteronuclear shift correlation. IR spectra were recorded on a Perkin–Elmer 1725-
X FT-IR spectrophotometer. Measurements of optical activity were performed using a Perkin–Elmer
142 spectropolarimeter and 1 dm tubes. Pd(PPh3)4 was prepared according to the literature.16 (R)-
Alpine-borane [[α]D20 −3.0 (neat)], [RuCl2(η6-p-cymene)]2 and bis(dibenzylideneacetone)palladium(0)
[Pd(dba)2] were commercially available. (1R,2R)-N-(p-Toluenesulfonyl)-1,2-diphenylethylenediamine
[(R,R)-Ts-DPEN], [α]D25.5 −30.27 (c 0.413, CHCl3), was prepared from commercially available (1R,2R)-
1,2-diphenylethylene-diamine, [α]D20 +10.2 (c=1, EtOH), according to the literature.17 4-Ethynyltoluene
3 was prepared in 92% yield by reaction of 4-iodotoluene with ethynylmagnesium bromide in THF at
20°C in the presence of 5 mol% Pd(PPh3)4.12
3.1. 1-(p-Tolyl)-1-pentyn-3-one 5
A solution of compound 3 (9.05 g, 78.0 mmol) in THF (20 ml) was added dropwise to a 0.819 M THF
solution of ethynylmagnesium bromide (100 ml, 81.9 mmol) and the resulting mixture was refluxed for

R. Rossi et al. / Tetrahedron: Asymmetry 10 (1999) 1163–1172
1169
1 h. It was then cooled to room temperature and added to a stirred solution of dry ZnBr2 (22.8 g, 101.5
mmol) in THF (100 ml) which was cooled to 0°C. The resulting suspension was stirred at 0°C for 2 h.
Pd(PPh3)4 (3.46 g, 2.99 mmol) and a solution of propionyl chloride (5.55 g, 60.0 mmol) in THF (50
ml) were then sequentially added and the resulting mixture was stirred for 4 h at 0°C and for 1.5 h at
20°C. The reaction mixture was quenched with a large excess of a saturated aqueous NH4Cl solution,
extracted with Et2O, dried over Na2SO4, filtered over Celite and concentrated in vacuo. The residue was
diluted with a mixture of hexane and benzene (50 ml, 60:40) and filtered over Celite. The filtrate was
concentrated in vacuo and the residue was purified by MPLC on silica gel, using a mixture of hexane and
benzene (60:40) as an eluent, to give chemically pure 5 (8.40 g, 81% yield based on propionyl chloride)
as a colorless solid: m.p. 34–36°C. MS, m/z (%): 172 (21), 143 (96), 142 (100), 115 (27), 89 (23). IR
(KBr): ν 2196, 1671, 1603, 1509, 1459, 1405, 1343, 1114, 821, 796 cm−1. 1H NMR (200 MHz, CDCl3):
δ 7.46 (2H, d, J=8.0 Hz, H-30 and H-50), 7.18 (2H, d, J=8.0 Hz, H-20 and H-60), 2.68 (2H, q, J=7.4 Hz,
H-4), 2.38 (3H, s, H-7), 1.21 ppm (3H, t, J=7.4 Hz, H-5). Anal. calcd for C12H12O: C, 83.87; H, 7.02.
Found: C, 84.09; H, 7.27.
3.2. (RS)-1-(p-Tolyl)-1-pentyn-3-ol (RS)-2a
Sodium borohydride (2.30 g, 6.08 mmol) was added during 20 min to a solution of compound 5 (3.50
g, 20.35 mmol) in 2-propanol (100 ml) which was stirred at 0°C. After stirring the reaction mixture for 1
h at 0°C, acetone (60 ml) was added dropwise and the resulting mixture, which was maintained at 0°C,
was treated with 10% aqueous HCl (170 ml) and then diluted with CH2Cl2 (70 ml). It was then allowed to
warm up to room temperature and extracted repeatedly with CH2Cl2. The collected organic extracts were
washed with water, diluted aqueous NaHCO3 solution and water, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by MPLC on silica gel, using a mixture of CH2Cl2 and hexane (70:30) as
an eluent, to give chemically pure (RS)-2a (2.90 g, 82% yield) as a pale yellow liquid. MS, m/z (%): 174
(25), 156 (10), 144 (95), 115 (100), 91 (49). IR (film): ν 2232, 1510, 1463, 1456, 1099, 1049, 1020, 963,
817 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.326 (2H, d, J=8.2 Hz, H-30 and H-50), 7.107 (2H, d, J=8.2
Hz, H-20 and H-50), 4.543 (1H, t, J=6.4 Hz, H-3), 2.342 (3H, s, H-70), 1.820 (2H, m, H-4), 1.075 ppm
(3H, t, J=7.3 Hz, H-5). 13C NMR (150 MHz, CDCl3): δ 138.43 (C-40), 131.55 (C-30 and C-50), 128.99
(C-20 and C-60), 119.57 (C-10), 89.25 (C-2), 85.00 (C-1), 64.21 (C-3), 31.00 (C-2), 21.72 (C-70), 9.47
ppm (C-5). 1H NMR (600.13 MHz, D2O): δ 7.438 (2H, d, J=8.4 Hz, H-30 and H-50), 7.270 (2H, d, J=8.4
Hz, H-20 and H-60), 4.605 (1H, t, J=7.1 Hz, H-3), 2.368 (3H, s, H-70), 1.810 (2H, quint, J=7.1 Hz, H-4),
1.502 ppm (3H, t, J=7.1 Hz, H-5). 1H NMR (600.13 MHz, saturated solution of α-CD in D2O): δ 7.683
(2H, d, H-30 and H-50), 7.353 (2H, d, H-20 and H-60), 4.515 (0.5H, t, H-3), 4.470 (0.5H, t, H-3), 2.439
(3H, s, H-70), 1.725 (2H, quint, H-4), 1.039 (1.5H, t, H-5) and 1.032 ppm (1.5H, t, H-5). Anal. calcd for
C12H14O: C, 82.72; H, 8.10. Found: C, 82.66; H, 8.23.
3.3. Synthesis of (R)-1-(p-tolyl)-1-pentyn-3-ol (R)-2a by enantioselective reduction of 5 with (R)-alpine-
borane
A solution of compound 5 (3.50 g, 20.35 mmol) in deaerated dry THF (15 ml) was added dropwise to
a 0.5 M THF solution of (R)-alpine-borane (57.0 ml, 28.50 mmol) and the resulting mixture was stirred
under argon for 46 h at 20°C. It was then cooled to 0°C, acetaldehyde (1.2 ml, 21.4 mmol) was added
and the solution was stirred at 0°C for 0.5 h. The solution was then allowed to warm up to 20°C and THF
was removed at 20 torr. The reaction vessel was then filled with argon and the liquid residue, which was
stirred at 35–40°C was maintained at 0.05 torr for 3.5 h in order to remove α-pinene liberated during

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the reaction. The reaction vessel was then filled with argon, the liquid residue was diluted with dry Et2O
(60 ml) and the resulting solution was cooled to 0°C. Ethanolamine (1.73 ml, 28.47 mmol) was added
and a white solid precipitated. The mixture was stirred for 1 h at 0°C and then filtered over Celite. The
collected solid was washed with cold Et2O. The collected filtrates were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel, using a mixture of
22
CH2Cl2 and hexane (70:30) as an eluent, to give chemically pure (R)-2a (3.07 g, 86.7% yield): [α]D
+14.54 (c 1.04, Et2O). The spectral properties of this compound were in good agreement with those
of (RS)-2a. The enantiomeric purity of (R)-2a was estimated to be 88.7% by HPLC analysis [column:
Chiralcel OJ; solvent: hexane:2-propanol (90:10); flow rate: 0.5 ml/min; detection at 254 nm]; tR=17.3
min (>94.3%) [(S)-2a; tR=22.6 min (<5.6%)].
3.4. Synthesis of (R)-1-(p-tolyl)-1-pentyn-3-ol (R)-2a by asymmetric transfer hydrogenation of 5 by a
chiral ruthenium(II) complex
A flame dried reaction vessel, which was maintained under an argon atmosphere, was charged with
[RuCl2(η6-p-cymene)]2 (40.83 mg, 0.066 mmol), (R,R)-TsDPEN (48.80 mg, 0.133 mmol) and deaerated
2-propanol (15 ml) and the mixture was stirred at room temperature. A 1.51 M solution of KOH in
2-propanol (200 µl, 0.332 mmol) and a solution of compound 5 (3.44 g, 20.0 mmol) in deaerated 2-
propanol (25 ml) were sequentially added and the resulting solution, which was a deep purple color, was
stirred under argon at 28°C for 4.5 h. It was then concentrated in vacuo and the residue was purified by
MPLC on silica gel, using a mixture of CH2Cl2 and hexane (70:30) as an eluent, to give chemically pure
22
1
(R)-2a (3.0 g, 86.2% yield): [α]D +15.91 (c 0.993, Et2O). H NMR (600.13 MHz, saturated solution
of α-CD in D2O): δ 7.683 (2H, d, H-30 and H-50), 7.353 (2H, d, H-20 and H-60), 4.470 (1H, t, H-3),
2.439 (3H, t, H-70), 1.725 (2H, quint, H-4), 1.039 ppm (3H, t, H-5). A triplet at δ 4.515 and a triplet at
δ 1.032, which were assigned to the H-3 and H-5 protons of (S)-2a, respectively, were also detected in
this 1H NMR spectrum. The spectral properties of (R)-2a were in good agreement with those of (RS)-2a.
The enantiomeric purity of (R)-2a was estimated to be 96.8% by HPLC analysis [column: Chiralcel OJ;
solvent: hexane:2-propanol (90:10); flow rate: 0.5 ml/min; detection at 254 nm]; tR=17.3 min (98.4%)
[(S)-2a; tR=22.6 min (1.6%)]. On the other hand, the e.e. of (R)-2a was estimated to be ca. 99% on the
basis of its 1H NMR spectrum registered in a D2O solution which was saturated with α-CD.
3.5. (RS)-Incrustoporin (RS)-1a
A mixture of compound (RS)-2a (2.56 g, 14.71 mmol), Pd(dba)2 (0.677 g, 1.18 mmol), dppb (0.502 g,
1.18 mmol) and deaerated anhydrous CH2Cl2 (100 ml) was reacted with carbon monoxide (600 psi) and
hydrogen (200 psi) at 95°C in a stainless steel autoclave for 48 h. After the autoclave was cooled to room
temperature, the gases were released and the crude rection mixture was filtered over Celite. The filtrate
was concentrated in vacuo, the residue was diluted with a mixture of hexane and THF (50 ml, 90:10)
and filtered over Celite. The filtrate was concentrated in vacuo and the residue was purified by MPLC on
silica gel using a mixture of hexane and THF (90:10) as an eluent, to give chemically pure (RS)-1a (2.01
g, 67.6% yield) as a colorless solid: m.p. 53–55°C. MS, m/z (%): 202 (15), 145 (19), 117 (100), 91 (14),
1
57 (11). IR (KBr): ν 1752, 1514, 1337, 1117, 966, 825, 733 cm−1. H NMR (600.13 MHz, CDCl3): δ
7.756 (2H, d, J=8.2 Hz, H-9 and H-13), 7.488 (1H, d, J=1.9 Hz, H-4), 7.219 (2H, d, J=8.2 Hz, H-9 and
H-13), 7.488 (1H, dt, J=1.9 and 6.2 Hz, H-5), 2.376 (3H, s, H-14), 1.876 (1H, m, H-6), 1.796 (1H, m,
H-6), 1.061 ppm (3H, t, J=7.5 Hz, H-7). 13C NMR (150 MHz, CDCl3): δ 171.90 (C-2), 146.56 (C-4),
139.40 (C-11), 131.76 (C-3), 129.33 (C-10 and C-12), 127.19 (C-9 and C-13), 126.42 (C-8), 81.42 (C-

R. Rossi et al. / Tetrahedron: Asymmetry 10 (1999) 1163–1172
1171
5), 24.78 (C-6), 21.36 (C-14), 9.184 ppm (C-7). These spectral data were in satisfactory agreement with
those reported for the natural product.2 1H NMR (600.13 MHz, D2O): δ 7.909 (1H, d, J=1.5 Hz, H-4),
7.709 (2H, d, J=8.8 Hz, H-9 and H-13), 7.365 (2H, d, J=8.2 Hz, H-10 and H-12), 5.271 (1H, dt, J=1.5
and 5.5 Hz, H-5), 2.398 (3H, s, H-14), 1.957–1.864 (2H, m, H-6), 1.000 ppm (3H, t, J=7.5 Hz, H-7). 1H
NMR (600.13 MHz, saturated solution of β-CD in D2O): δ 7.732 (0.5H, d, H-4), 7.721 (0.5H, d, H-4),
7.670 (1H, d, H-9 and H-13), 7.664 (1H, d, H-9 and H-13), 7.331 (2H, d, H-10 and H-12), 5.347 (0.5H,
dt, H-5), 5.340 (0.5H, dt, H-5), 2.430 (3H, s, H-14), 2.055 (1H, m, H-6), 1.893 (1H, m, H-6), 0.983 ppm
(3H, t, H-7).
3.6. (R)-Incrustoporin (R)-1a
22
The Pd-catalyzed cyclocarbonylation of 96.8% enantiomerically pure (R)-2a, [α]D +15.91 (c 0.993
Et2O), which was performed according to the same procedure used for the synthesis of (RS)-1a, provided
25
chemically pure (R)-1a in 68% yield. Compound (R)-1a had: m.p. 32–34°C (lit.3 m.p. 43°C); [α]D
−5.77 (c 3.156, CHCl3) [lit.2 [α]D −4 (c 0.3, CDCl3); lit.3 [α]D23 −6.8 (c 0.3, CHCl3)]. 1H NMR (600.13
MHz, saturated solution of β-CD in D2O): δ 7.732 (1H, d, H-4), 7.670 (2H, d, H-9 and H-13), 7.331 (2H,
d, H-10 and H-12), 5.340 (1H, dt, H-5), 2.430 (3H, s, H-14), 2.055 (1H, m, H-6), 1.893 (1H, m, H-6),
0.893 ppm (3H, t, H-7). A doublet at δ 7.721, a doublet at δ 7.664 and a doublet of triplets at δ 5.347,
which were assigned to the H-4, H-13 and H-5 protons of (S)-1a, respectively, were also observed in
this 1H NMR spectrum. The enantiomeric purity of (R)-1a was estimated to be 95.2% by HPLC analysis
[Chiralcel OJ column; solvent: hexane:2-propanol (75:25); flow rate: 0.7 ml/min; detection at 254 nm];
tR 24.4 min (97.6%) [(S)-1a; tR=17.2 min (2.4%)]. On the other hand, the e.e. of (R)-1a was estimated
1
to be higher than 91% on the basis of its H NMR spectrum registered in a D2O solution which was
saturated with β-CD.
It must also be noted that the Pd-catalyzed cyclocarbonylation reaction of (R)-2a having [α]D22 +14.54
25
(c 1.04 Et2O) provided in 69% yield chemically pure (R)-1a which had: m.p. 32–35°C; [α]D −5.10 (c
3.126, CHCl3). The enantiomeric purity of this sample of (R)-1a was estimated to be 86.1% by HPLC
on a Chiralcel OJ column using the same experimental conditions employed for the HPLC analysis of
(R)-1a having [α]D25 −5.77 (c 3.156, CHCl3).
Finally, it is worth mentioning that although it has been reported that recrystallization of 94.5%
enantiomerically pure (R)-1a from hexane/ethyl acetate affords (R)-1a with an enantiomeric purity higher
than 99%,3 we made no attempt to increase, by recrystallization, the enantiomeric purity of (R)-1a which
had a value of 95.2% e.e.
Acknowledgements
We gratefully acknowledge the financial support from the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica (MURST) and the Progetto Finallizzato Beni Culturali (CNR, Roma). We wish
also to thank Prof. Annalaura Segre for the use of NMR facilities at the Servizio NMR dell’Area della
Ricerca di Roma (CNR, Roma).
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