What about BOB? A synthetically useful protecting group

Article abstract of DOI:10.1016/S0040-4039(00)01661-0

Benzyloxybutyryl (BOB) esters of alcohols can be prepared from commercially available 4-benzyloxybutyric acid by standard acylation techniques, by the Mitsunobu reaction (with inversion of configuration), or by the Jacobsen asymmetric nucleophilic ring opening of epoxides. BOB esters can be removed selectively in the presence of other esters under conditions that are compatible with a variety of sensitive functional groups. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01661-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9523–9526
What about BOB? A synthetically useful protecting group†
Matthew A. Clark and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca,
NY 14853-1301, USA
Received 2 September 2000; revised 14 September 2000; accepted 18 September 2000
Abstract
Benzyloxybutyryl (BOB) esters of alcohols can be prepared from commercially available 4-benzyloxy-
butyric acid by standard acylation techniques, by the Mitsunobu reaction (with inversion of configura-
tion), or by the Jacobsen asymmetric nucleophilic ring opening of epoxides. BOB esters can be removed
selectively in the presence of other esters under conditions that are compatible with a variety of sensitive
functional groups. © 2000 Elsevier Science Ltd. All rights reserved.
As part of a program in our laboratory aimed at the synthesis of novel monosaccharide
mimics, we have been interested in the keruffarides1 1 and crasserides2 2, a family of naturally-
occurring glycolipid mimics produced by marine sponges. We envisioned a retrosynthetic
strategy (Scheme 1) whereby 1 might arise from a suitably tetraprotected pentaol 3 by
O-alkylation. Intermediate 3 might come from protected epoxycyclopentanetriol 4 by an
asymmetric Jacobsen epoxide opening.3
Scheme 1.
* Corresponding author.
†
Dedicated with gratitude and appreciation to Professor Harry H. Wasserman on his 80th birthday; for his many
scholarly contributions, his leadership, and his unstinting service to our profession.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01661-0

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The Jacobsen reaction creates one of the two new hydroxyl groups in 3 as a carboxylate ester,
and it seemed attractive to use such an ester as a temporary blocking group while attaching the
glyceryl side chain. However, the final deprotection step must be compatible with the fatty acyl
ester in 1 and 2.
Removal of esters by lactonization is a common strategy, and has already been reported for
the 2-(2-benzyloxyethyl)benzoates.4,5 However, the starting material for this protecting group is
not readily available. Here we describe the synthesis and chemistry of 4-benzyloxybutyryl (BOB)
esters of alcohols. BOB esters, which do not appear to have been used as protecting groups in
synthesis, can be prepared in three ways from commercial 4-benzyloxybutyric acid (BOBOH):
(1) by direct esterification; (2) by the Mitsunobu reaction; or (3) by nucleophilic opening of
epoxides (the Jacobsen reaction). We further show that BOB esters undergo selective removal by
hydrogenolysis and lactonization in the presence of other esters and reducible functional groups.
Using standard dehydration conditions (EDC, DMAP, CH2Cl2), commercially available
alcohols 5, 7, 8, 11, 12 and 13 (Fig. 1) were condensed with BOBOH to furnish BOB esters 14,
16, 17, 20, 21 and 22 in good to excellent yields.6 Although the shelf life of these BOB esters was
not extensively studied, several representative examples showed no detectable change in NMR,
TLC or color after standing several months at rt. One notable exception was 22, which
underwent elimination of BOBOH upon standing at rt for several days to afford the correspond-
ing tropanol 2%-phenylacrylate ester (not shown). To investigate the formation of BOB esters by
the Mitsunobu reaction, alcohols 6 and 11 were reacted with diisopropylazodicarboxylate
(DIAD) and PPh3 in Et2O or THF as solvent. The desired BOB esters 15 and 20 were obtained
in moderate to good yields. In the case of 15, some product was lost as a result of additional
chromatography needed to remove unreacted DIAD.
Figure 1. Representative alcohols and their BOB esters
The synthetic plan we envisioned for 1 and 2 required that one BOB ester be installed by a
Jacobsen asymmetric epoxide opening. To test that strategy, BOBOH was reacted with
cyclohexene oxide following published conditions.3 Diol monoester 18 was isolated in 89% yield
as a pale yellow oil.7 Upon acetylation (Ac2O, pyr, CH2Cl2), 18 afforded the diester 19.

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Using 14 as a representative BOB ester, debenzylation proceeded smoothly using 10% Pd/C
as catalyst (1 atm H2, EtOAc). Hydrogenolysis was complete in 12–48 h, depending on the
quantities of Pd/C used, with optimal results achieved using 0.5–1.0 weight equiv. catalyst.
Release of butyrolactone from the resulting 4-hydroxybutyrate ester was tested using a variety
of bases. Very little butyrolactone was released using Et3N or DBU. However, addition of 10
mol% KOBut, which is known to promote lactonization,4 to a dry THF solution of 14
immediately generated 5.
Using the above described hydrogenolysis/cyclization conditions, BOB-derivatives 14, 15, 16,
18, 19 and 21 were successfully deprotected in high yield (Table 1). It is noteworthy that the free
alcohol in 18 did not significantly interfere with deprotection. Both the acetate moiety of 19 and
the methyl ester in 21 were stable to the deprotection conditions, confirming the hoped-for
utility of BOB esters in our synthetic approach to 1 and 2.
Table 1
Formation and deprotection of BOB esters
Entry
Starting material
Formation
methoda
BOB ester (% yield)
Deprotection
methodb
Alcohol (% yield)
1
2
3
4
5
6
7
8
9
5
6
7
8
A
B
A
A
14 (96)
15 (58)
16 (60)
17 (99)
18 (89)
19 (\95)
20 (90)
21 (89)
22 (87)
D
D
D
E
D
D
Ec
D
–
5 (90)
6 (90)
7 (93)
8 (91)
9 (94)
18 (91)
11 (84)
12 (92)
–
Epoxy-cyclohexane
C
18
11
12
13
Ac2O
A, B
A
A
a A=EDC, DMAP, CH2Cl2; B=DIAD, Ph3P, Et2O; C=Jacobsen’s catalyst, (iPr)2NEt, CH3OBut.
b D=(I) H2, 10% Pd/C, EtOAc or THF; (ii) 10 mol% KOBut, THF; E=(I) 1,4-cyclohexadiene, Pd, EtOH; (ii) 0.1
equiv. KOBut, THF.
c 1.1 equiv. of KOBut used in step (ii) of Method E.
In the case of BOB-derivatives 17 and 20, hydrogenolysis was accompanied by reduction of
the nitrile and alkene groups, respectively. However, by adopting catalytic transfer hydrogena-
tion conditions8 (Pd0, cyclohexadiene, EtOH), BOB ester 17 could be debenzylated without
affecting the cyano group. Base-catalyzed lactonization proceeded smoothly to give 8 in good
yield. In similar fashion, ester 20 was cleanly debenzylated without reduction of the heterocyclic
ring. Although the acidity of the imide N–H on the uracil ring necessitated the use of 1.1 equiv.
KOBut, unprotected nucleoside 11 was obtained in 84% yield.
Besides representing a practical implementation of the synthetic approach to keruffarides and
crasserides outlined earlier, the BOB group now provides a convenient method for deprotecting
an ester using a relatively non-nucleophilic base, through the agency of hydrogenolysis. In
addition, BOB esters may prove useful in designing new traceless linkers for solid-phase
chemistry.
Representative deprotection procedure: A solution of 16 (66 mg, 0.2 mmol) in THF (2 mL) was
added to 10% Pd/C (33 mg) and stirred for 24 h under 1 atm of H2 in a balloon. After filtering
the catalyst, the THF solution was dried (Na2SO4) and concentrated. The residue was dissolved

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in dry THF (1 mL) and treated with KOBut (1.0 M THF solution, 20 mL). After 10 min, the
reaction mixture was acidified with glacial acetic acid (40 mL), diluted with EtOAc (2 mL) and
washed with aqueous NaHCO3. After drying and concentrating, the residue was chro-
matographed (SiO2, 4:1 hexanes:EtOAc) to afford 1-adamantanol 7 (28 mg, 93%).
Acknowledgements
This work was supported by grants from the National Institutes of Health (grants GM 35712,
GM 08500). Support of the Cornell NMR Facility has been provided by NSF (CHE 7904825;
PGM 8018643) and NIH (RR02002).
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1
6. For 14: H NMR (300 MHz, CDCl3) l 7.36–7.16 (m, 10H), 4.47 (s, 2H), 4.27 (t, 2H, J=7 Hz), 3.47 (t, 2H J=7
Hz), 2.91 (t, 2H, J=7 Hz), 2.41 (t, 2H, J=7 Hz), 1.91 (m, 2H); 13C NMR (75 MHz, CDCl3) l 173.7, 138.7, 129.2,
128.7, 128.6, 128.5, 127.9, 127.8, 126.8, 73.1, 69.4, 65.1, 35.4, 31.4, 25.3; IR (umax film) 2870, 1735 cm−1; FIMS m/z
1
298 (M+, 100%). For 17: H NMR 7.34–7.25 (m, 5H), 4.87 (m, 1H), 4.49 (s, 2H), 3.51 (t, 2H, J=6 Hz), 2.62 (m,
1H), 2.47 (t, 2H, J=6 Hz), 2.16–1.90 (m, 4H), 1.80–1.20 (m, 6H); 13C NMR 173.4, 139.4, 129.4, 128.8, 128.7,
121.0, 74.0, 72.3, 70.1, 34.7, 32.3, 31.3, 28.9, 26.2, 24.6, 23.8; IR 2940, 2240, 1745 cm−1; FIMS m/z 301 (M+, 100%).
1
For 21: H NMR 7.37–7.29 (m, 5H), 5.33 (br. d, 1H), 4.54 (m, 1H), 4.48 (s, 2H), 4.45–4.27 (m, 2H), 3.73 (s, 3H),
3.47 (t, 2H, J=6 Hz), 2.42 (t, 2H, J=6 Hz), 1.90 (m, 2H), 1.43 (s, 9H); 13C NMR 174.0, 171.4, 156.2, 139.3, 129.4,
128.7, 81.3, 74.0, 70.1, 65.2, 53.9, 53.8, 32.0, 29.3, 26.0; IR 3365, 1746, 1715 cm−1; EIMS m/z 396 (M+1, 15%), 42
(100%).
1
7. For 18: H NMR 7.36–7.25 (m, 5H), 4.55 (m, 1H), 4.48 (s, 2H), 3.51 (m, 3H), 2.80 (br. s, 1H), 2.45 (m, 2H), 1.99
(m, 4H), 1.67 (m, 2H), 1.26 (m, 4H); 13C NMR 173.9, 138.4, 128.6, 128.0, 127.9, 78.3, 73.2, 72.8, 69.5, 33.1, 32.2,
30.2, 25.5, 24.2, 24.0; IR 3450, 1725 cm−1; ESI-MS m/z 293 (M+1, 20%), 41 (100%).
8. Felix, A. M.; Hiemer, E. P.; Lambros, T. J.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1978, 43, 4194–4196.
.