Asymmetric synthesis of α- And β-Benzylhydroxy-γ- butyrolactones

Article abstract of DOI:10.1055/S-0029-1218529

Herein we describe a new asymmetric synthesis of αbenzyl-α- hydroxy-γ-butyrolactone, a core building block of new HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimic. Immediate access to β-benzyl-β-hydroxy-γ-butyrolactone is also possible from a common intermediate. Both lactones are useful building blocks in their own right. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218529

LETTER
131
Asymmetric Synthesis of a- and b-Benzylhydroxy-g-butyrolactones
Asymmetric
a
e
-
and
b
-Be
n
d
zylhydroxy-
r
g
-butyro
o
lactones Pinho,* Mikael Pelcman, Tatiana Agback, Bertil Samuelsson
Medivir AB, Box 1086, 141 22 Huddinge, Sweden
Fax +46(8)54683199; E-mail: pedro.pinho@medivir.se
Received 14 September 2009
non-prime side
prime side
R1
Abstract: Herein we describe a new asymmetric synthesis of a-
benzyl-a-hydroxy-g-butyrolactone, a core building block of new
HIV-1 protease inhibitors containing a tertiary alcohol in the transi-
tion-state mimic. Immediate access to b-benzyl-b-hydroxy-g-butyro-
lactone is also possible from a common intermediate. Both lactones
are useful building blocks in their own right.
P1'
O
O
N
O
H
N
Key words: lactones, asymmetric catalysis, epoxidations, oxida-
tions, HIV
N
N
H
OH
H
HO
P2
O
Ph
P1
We have recently reported on new HIV-1 protease inhib-
itors containing a tertiary alcohol in the transition-state
mimic A (Figure 1).1 The central core of this type of in-
hibitor can be prepared by either epoxidation of 1 and sub-
sequent ring opening1a–1c or by the opening of a-benzyl-a-
hydroxy-g-butyrolactone (2) with the appropriate amino
alcohol.1d Unfortunately, both these methods require sep-
aration of diastereomers, which is not always possible and
does not allow the use of non-chiral amino alcohols in P2
variations. A survey of the literature revealed only one
asymmetric preparation of 2,2 and this approach gave low
enantiomeric excesses of only 48 to 50%. Other aryl and
alkyl substituents are rare in the literature.3
A
O
O
Ph
O
N
H
OH
HO
Ph
1
rac-2
Figure 1 HIV-1 protease inhibitors A and core building blocks
elsewhere4 yielded compound 3. The lactone was then
opened with a slight excess of NaOH and the acid was
trapped as the corresponding 2-propyl ester. Alcohol 4
was protected with TBDMS under standard conditions
and the ester was reduced to the allylic alcohol 5 with
DIBAL-H.
Therefore, in order to allow the study of further variations
of the P2 unit and for practical purposes when preparing
larger amounts of compound, an asymmetric synthesis of
one of the core building blocks was designed (Scheme 1).
As in the racemic synthesis of 2,1d simple condensation of
g-butyrolactone with benzaldehyde as reported
O
O
OH
OTBDMS
a
b
O
O
HO
86%
63%
Ph
Ph
Ph
c
3
5
4
87%
OTBDMS
OTBDMS
d
HO
HO
OH
O
99%
Ph
Ph
7, 94%ee
6
Scheme 1 Reagents and conditions: (a) i. NaOH (1.5 equiv), THF–H2O (1:1), r.t., 1 h; ii. dry ice, r.t., 15 min; 2-iodopropane (1.5 equiv),
DMSO, r.t., 20 h; (b) i. TBDMSCl (1.5 equiv), imidazole (2.5 equiv), DMF, 0 °C → r.t., 90 min; ii. DIBAL-H (3 equiv), Et2O, –78 °C, 2 h; iii.
sat. di-potassium tartrate, 90 min, r.t.; (c) Ti(i-PrO)4 (8 mol%), (+)-DIPT (10 mol%), t-BuOOH (2 equiv), 4 Å MS, CH2Cl2, –20 °C, 5 h; (d) 10
wt% Pd/C (10 wt%), H2 (1 atm), 20 h.
SYNLETT 2010, No. 1, pp 0131–0133
x
x.
x
x.
2
0
0
9
Advanced online publication: 30.11.2009
DOI: 10.1055/s-0029-1218529; Art ID: G30309ST
© Georg Thieme Verlag Stuttgart · New York

132
P. Pinho et al.
LETTER
(2) Curran, D. P.; Ku, S.-B. J. Org. Chem. 1994, 59, 6139.
Chirality was then introduced using Sharpless asymmetric
epoxidation.5 Catalytic hydrogenation of the resulting ep-
oxide 6 yielded diol 7, which was treated with (R)-(+)-a-
methoxy-a-(trifluoromethyl)phenyl acetic acid to afford
the corresponding Mosher ester.6 The enantiomeric ex-
cess of the epoxidation step was then determined by inte-
gration of the 19F NMR spectra and showed to be 94%.
The process was then scaled up to produce 50 grams of the
convenient precursor 7.
Direct oxidation of 7 with Pt/C and oxygen7 (Scheme 2)
produced a lactone that was physically non-identical to ra-
cemic 2. Careful NMR analysis revealed the presence of
lactone 8,8 which was formed through loss of the silyl pro-
tection under the reaction conditions and oxidation of the
less hindered alcohol; this conclusion was supported by
observation of the intermediate triol by LC-MS analysis
during the course of the reaction.
(3) (a) For Me, using chiral auxiliary strategy, see: Davis, F. A.;
Reddy, G. V.; Chen, B.-C.; Kumar, A.; Haque, M. S. J. Org.
Chem. 1995, 60, 6148. (b) For Me, Et, n-Pr and i-Pr using a
seven-step sequence from (–)-ephedrine, see: Pansare, S. V.;
Jain, R. P.; Ravi, R. G. Tetrahedron: Asymmetry 1999, 10,
3103. (c) For Me, from (–)-malic acid, see: Ohba, M.; Izura,
R.; Shimizu, E. Tetrahedron Lett. 2000, 41, 10251.
(d) Ohba, M.; Izura, R.; Shimizu, E. Chem. Pharm. Bull.
2006, 54, 63. (e) Scherkenbeck, J.; Barth, M.; Thiel, U.;
Metten, K.-H.; Heinemann, F.; Welzel, P. Tetrahedron
1988, 44, 6325. (f) Sugai, T.; Kakeya, H.; Ohta, H.
Tetrahedron 1990, 46, 3463. (g) For Ph, see: Yazaki, R.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
3195. (h) Eliel, E. L.; Bai, X.; Ohwa, M. J. Chin. Chem. Soc.
2000, 47, 63. (i) Frongia, A.; Girard, C.; Ollivier, J.; Piras,
P. P.; Secci, F. Synlett 2008, 2823.
(4) See, for example: Yato, M.; Homma, K.; Ishida, A.
Tetrahedron 2001, 57, 5353.
(5) The procedure used was similar to that reported, see: Gao Y.,
Hanson R. M., Klunder J. M., Ko S. Y., Masamune H.,
Sharpless K. B.; J. Am. Chem. Soc.; 1987, 109: 5765; Note:
Performing the reaction under non-anhydrous conditions
leads to extended reaction times and lower
O
O
O
b
a
7
enantioselectivity.
61%
66%
OH
OH
O
(6) Following the reported procedure a racemic sample of 7 was
prepared through oxidation of 5 with m-CPBA. The Mosher
ester of this sample was also prepared for comparison of the
19F NMR spectra. See: Akhoon, K. M.; Myles, D. C. J. Org.
Chem. 1997, 62, 6041.
Ph
Ph
2
8
Scheme 2 Reagents and conditions: (a) i. 5 wt% Pt/C (40 wt%), air,
NaHCO3, H2O, EtOAc, i-PrOH, 70 °C, 24–48 h; ii. 2 M H2SO4; (b) i.
Et3N (3 equiv), SO3·pyridine complex (1.1 equiv), CH2Cl2–DMSO
(3:1), 0 °C → r.t., 1 h; ii. NaClO2 (2 equiv), NaHCO3 (2.5 equiv), 2-
methylbut-2-ene (1.1 equiv), t-BuOH–H2O (3:1), r.t., 2 h; iii. concd
HCl, MeOH–H2O (4:1), r.t., 15 min.
(7) See for example: Bennani, Y. L.; Vanhessche, K. P. M.;
Sharpless, K. B. Tetrahedron: Asymmetry 1994, 5, 1473.
(8) (a) For racemic 8 see: Plattner, P. A.; Heusser, H. Helv.
Chim. Acta 1945, 28, 1044. (b) For Me through biotrans-
formation, see: Holland, H. L.; Gu, J.-X. Biotechnol. Lett.
1998, 20, 1125. (c) For Me and Ph, see reference 3h;
(d) Typical experimental procedure for the oxidation of 7 to
8: A two-neck flask fitted with a reflux condenser was
loaded with 7 (93 mg, 0.30 mmol) and EtOAc (4 mL). To the
stirring solution was added NaHCO3 (30 mg), H2O (4 mL)
and 2-PrOH (0.80 mL). Pt/C (5 wt%, 40 mg) was added and
the mixture heated at 70 °C for 24 to 48 h while bubbling air
through a gas dispersion tube. NOTES: 1) the reaction is
considerably faster using oxygen, but the combination of O2
and Pt(0) can easily cause fire and should be carefully
controlled. 2) The transformation should be carefully
monitored by LC-MS since, due to the four phase system,
reaction times can vary. When complete, or nearly complete,
the mixture was cooled to r.t. and the catalyst was filtered
off. Organic solvents were removed by evaporation and
MeOH (equal volume to that of H2O) was added. The
solution was acidified with 2 M H2SO4 and stirred for 30
min. The solution was diluted with EtOAc (20 mL) and
poured into an extraction funnel. The organic phase was
washed with H2O (4 × 5 mL), dried over Na2SO4, filtered
and concentrated. Flash chromatography on silica gel
(EtOAc–hexane, 40%) yielded 8 (38 mg, 66%). [a]D20 –49.9
(c 1.4, MeOH); 1H NMR (400 MHz, CDCl3): d = 7.19–7.40
(m, 5 H), 4.11–4.32 (m, 2 H, g-CH2), 2.97–3.02 (m, 2 H, b-
Bn-CH2), 2.44–2.73 (m, 2 H, a-CH2), 2.27 (br s, 1 H, OH);
13C NMR (100 MHz, CDCl3): d = 175.3, 134.9, 129.8, 129.0,
127.6, 77.9, 76.8, 43.9, 41.9. The structure was confirmed
through conventional gHMBC experiments. The 1D 1H
NMR spectrum shows three different sets of CH2 protons.
The first observed quartet at d = 4.11–4.32 ppm was
assigned to the g-CH2 due to the largest downfield chemical
shift when compared to the others. Furthermore it also shows
Compound 7 was therefore stepwise oxidized, first to the
aldehyde and then to the acid9 to afford, after deprotec-
tion, the desired lactone. Compound 2 was then used for
the synthesis of inhibitor A, which showed spectroscopic
data similar to those observed previously, thereby con-
firming the absolute stereochemistry of the lactone pro-
duced by the process described here.
In conclusion, an asymmetric synthesis of both a- and b-
benzylhydroxy-g-butyrolactone has been developed. This
has allowed us to further screen P2 variations on our fam-
ily of HIV-1 protease inhibitors beyond chiral amino alco-
hols, as well as to produce larger amounts of selected
compounds for extended biological studies.
References and Notes
(1) (a) Ekegren, J. K.; Unge, T.; Safa, M. Z.; Wallberg, H.;
Samuelsson, B.; Hallberg, A. J. Med. Chem. 2005, 48, 8098.
(b) Ekegren, J. K.; Gising, J.; Wallberg, H.; Larhed, M.;
Samuelsson, B.; Hallberg, A. Org. Biomol. Chem. 2006, 4,
3040. (c) Ekegren, J. K.; Ginman, N.; Johansson, Å.;
Wallberg, H.; Larhed, M.; Samuelsson, B.; Unge, T.;
Hallberg, A. J. Med. Chem. 2006, 49, 1828. (d) Ekegren,
J. K.; Hallberg, A.; Wallberg, H.; Samuelsson, B.; Kannan,
M. WO 2006/084688, 2006. (e) Wu, X.; Öhrngren, P.;
Ekegren, J. K.; Unge, J.; Unge, T.; Wallberg, H.;
Samuelsson, B.; Hallberg, A.; Larhed, M. J. Med. Chem.
2008, 51, 1053.
Synlett 2010, No. 1, 131–133 © Thieme Stuttgart · New York

LETTER
a weak three-bond interaction with the carbonyl carbon in
Asymmetric a-and b-Benzylhydroxy-g-butyrolactones
133
aldehyde was dissolved in t-BuOH (25 mL). To the solution
were added H2O (5 mL), NaHCO3 (2.5 equiv), 2-methyl-2-
butene (1.1 equiv) and NaClO2 (2.1 equiv). After stirring for
2 h the solvent was removed, the residue was taken into
EtOAc (75 mL) and the pH was adjusted to 2 with 0.5 M
NaHSO4. Upon phase separation the solvent was removed
and the crude acid was taken into MeOH (20 mL). H2O (5
mL) was added and the stirring mixture was treated with
concd HCl (6 mL). After 15 min the reaction was evaporated
to dryness and the residue was purified by flash chromatog-
raphy on silica gel (EtOAc–hexane, 40%) to yield 2 (800
mg, 61%). [a]D20 –72.6 (c 1.5, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d = 7.22–7.36 (m, 5 H), 4.24–4.31 (m, 1 H), 3.73–
3.81 (m, 1 H), 3.06 (s, 1 H), 2.89 (s, 1 H), 2.25–2.41 (m,
2 H); 13C NMR (100 MHz, CDCl3): d = 178.8, 134.2, 130.0,
128.7, 127.5, 73.3, 65.2, 43.5, 34.0; LC-MS (ESI+): m/z =
the gHMBC spectrum. The second set, a collapsed quartet at
d = 2.97–3.02 ppm, shows interaction with the aromatic
carbons in the gHMBC spectrum, and was therefore
assigned to the b-Bn-CH2. Finally, the observed quartet at
higher field, d = 2.44–2.73 ppm was assigned to the a-CH2,
showing a strong two-bond interaction with the carbonyl
carbon in the gHMBC spectrum. LC-MS (ESI+): m/z = 193
+
[M + 1], 210 [M+NH4 ].
(9) Typical experimental procedure for the oxidation of 7 to 2:
To a cold (0 °C) solution of 7 (2.12 g, 6.83 mmol) in
CH2Cl2–DMSO (3:1, 20 mL) was added Et3N (3 equiv)
followed by SO3·pyridine complex (1.1 equiv). The ice bath
was removed and the reaction was allowed to stir at r.t. for
1 h. The solution was then poured into an extraction funnel,
diluted with EtOAc (50 mL) and washed with brine (3 × 10
mL). The solvent was removed by evaporation and the crude
+
193 [M + 1], 210 [M + NH4 ].
Synlett 2010, No. 1, 131–133 © Thieme Stuttgart · New York

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