Selective and Practical Synthesis of Penciclovir

Article abstract of DOI:10.1081/SCC-120026312

A selective and practical method has been developed for the synthesis of penciclovir (1) in gram quantities involving a highly N⁹ selective alykylation of 2-amino-6-chloropurine (9) with 2-(2-phenyl-1,3-dioxane-5-yl)ethanol (12) as a key step.

Full text of DOI:10.1081/SCC-120026312

This article was downloaded by: [Georgetown University]
On: 23 August 2013, At: 11:45
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Selective and Practical Synthesis of Penciclovir
Tatsushi Toyokuni a , Joseph C. Walsh a , Mohammad Namavari a , Shirin S. Shinde a , Jennifer
R. Moore a , Jorge R. Barrio a & Nagichettiar Satyamurthy a
a Crump Institute for Molecular Imaging, Department of Molecular and Medical
Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Published online: 19 Aug 2006.
To cite this article: Tatsushi Toyokuni , Joseph C. Walsh , Mohammad Namavari , Shirin S. Shinde , Jennifer R. Moore , Jorge
R. Barrio & Nagichettiar Satyamurthy (2003) Selective and Practical Synthesis of Penciclovir, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:22, 3897-3905, DOI: 10.1081/
SCC-120026312
To link to this article: http://dx.doi.org/10.1081/SCC-120026312
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3897–3905, 2003
Selective and Practical Synthesis
of Penciclovir
*
Tatsushi Toyokuni, Joseph C. Walsh, Mohammad Namavari,
Shirin S. Shinde, Jennifer R. Moore, Jorge R. Barrio,
and Nagichettiar Satyamurthy
Crump Institute for Molecular Imaging,
Department of Molecular and Medical Pharmacology,
David Geffen School of Medicine at UCLA, Los
Angeles, California, USA
ABSTRACT
A selective and practical method has been developed for the synthesis
of penciclovir (1) in gram quantities involving a highly N9 selective
alykylation of 2-amino-6-chloropurine (9) with 2-(2-phenyl-1,3-
dioxane-5-yl)ethanol (12) as a key step.
Key Words: Alkylation; Penciclover; Practical; Selective; Synthesis.
*Correspondence: Tatsushi Toyokuni, LA Tech Center, Department of
Molecular and Medical Pharmacology, David Geffen School of Medicine at
UCLA, 6140 Bristol Parkway, Culver City, CA 90230, USA; Fax: 310-670-
8428; E-mail: ttoyokuni@mednet.ucla.edu.
3897
DOI: 10.1081/SCC-120026312
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3898
Toyokuni et al.
INTRODUCTION
Penciclovir[1] is a widely used drug for the treatment of herpes
virus infections[1] (Fig. 1). Since the first synthesis by Pandit et al. in
1972,[2] a number of methods have been developed for the preparation
of 1.[3] Among them the method reported by Harnden et al. in 1985[3a,b]
remains the most concise route from commercially available starting
compounds. However, two key steps in this method are rather inefficient
and make the procedure less attractive. For example, the protection of
1,3-diol functionality in compound 3 (Sch. 1) as the acetonide derivative
yields a mixture of products 4 and 5 in a ratio of ꢀ4:1. The required
acetonide 4 is separated from the unwanted derivative 5 by column
chromatography. Secondly, alkylating agent 6 derived from the
alcohol 4 when reacted with the chloropurine 9 also yields a mixture
of N9 and N7 alkylated products 10 and 11, respectively, which are
separated by column chromatography. To obviate these shortcomings
a newer procedure has recently been introduced.[3e] In this method
the 1,3-diol function is protected as a cyclic acetal containing a
bulky tert-butyl group (Sch. 1, products 7 and 8) to enhance N9 regios-
electivity during the alkylation of 9. However, in this method also a
significant amount (ꢀ10%) of the undesirable N7 alkylation product
was formed.
As a part of our on-going research program,[4] we required
penciclovir in gram quantities on a regular basis. We have developed
an efficient synthesis of 1 involving a highly N9 selective alkylation
procedure. To the best of our knowledge this method provides the
highest N9 regioselectivity for the alkylation to yield 1. Described
herein is a practical method suitable for a large-scale synthesis of
penciclovir.
Figure 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of Penciclovir
3899
Scheme 1. (a) NaBH4, t-BuOH, MeOH; (b) 2,2-dimethoxypropane, TsOH,
THF; (c) CBr4, PPh3, DMF; (d) trimethylacetaldehyde, TsOH, THF; (e)
(1) MsCl, Et3N, (2) NaI, acetone; (f) K2CO3, DMF.
RESULTS AND DISCUSSION
Scheme 2 delineates the synthesis of penciclovir developed in our
laboratories. The triol 3 was synthesized in 79% yield from the triester
2 (Sch. 1) using the NaBH4/t-BuOH/MeOH system.[5] The crude product
was purified with the aid of anion- and cation exchange resins.[6] Since
ion-exchange resins can be regenerated repeatedly, the resin-based
purification is particularly suited for the preparative-scale synthesis
because of its simplicity.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3900
Toyokuni et al.
Scheme 2. (a) Benzaldehyde dimethyl acetal, TsOH, THF; (b) CBr4, PPh3,
DMF; (c) K2CO3, DMF; (d) 2 M HCl.
Benzylidene acetal, which is readily formed in high yields by a
reaction with commercially available benzaldehyde dimethyl acetal, is
commonly used for selective protection of 1,3-diols in carbohydrate
chemistry.[7] The triol 3 was treated with benzaldehyde dimethyl acetal
in the presence of TsOH at room temperature to yield the expected
1,3-dioxane 12[8] as the sole product in 80–85% yields. As expected, the
1H NMR spectrum indicated that 12 was produced as a mixture of cis
and trans isomers in a ratio of approximately 1:3. The trans isomer was
readily identified based on the splitting patterns of the signals at ꢀ 3.59
(pseudo t, 2H, J ¼ 11 Hz) and ꢀ 4.27 (dd, 2H, J ¼ 11 and 4 Hz), which
are characteristic of two equivalent axial (H-4ax and H-6ax) and two
equivalent equatorial protons (H-4eq and H-6eq) having a vicinal axial
proton (H-5) in a chair conformation. On the other hand, the proton
NMR spectrum of the cis isomer suggested that it probably adopts a
distorted or nonchair conformation.
Treatment of the alcohol 12 with CBr4 and Ph3P yielded the
1
benzylidene-protected bromide 13 in 81% yield. The H NMR spectrum
revealed that the product is a 1:1.5 mixture of cis and trans isomers, as a
result of equilibration of the cis and trans isomers during the
bromination.[9] Because of deterioration during storage, the bromide 13
was used shortly after preparation.
Alkylation of 2-amino-6-chloropurine (9) was carried out using 0.9
equivalent of 13 in anhydrous DMF.[10] TLC analysis of the reaction
mixture indicated a complete consumption of 13 and the formation of
two closely migrating products, which were isolated in ꢀ95% yield as a
mixture by silica-gel column chromatography. The 1H NMR spectra

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of Penciclovir
3901
showed that these two products were cis and trans isomers in a ratio
of approximately 1:1.5. However, we could not determine the site of
1
alkylation even though H NMR has previously been successfully used
to characterize the position (N9 vs. N7) of alkylation.[11] Since the
alkylated product 14 was isolated near quantitatively, the position of
the alkylation was determined after its transformation to the final
product 1. Thus, the mixture of cis and trans isomers was hydrolyzed
with 2 M HCl to afford a single product in 80–85% yield, whose 1H NMR
spectrum in DMSO-d6 and UV spectrum in H2O were in good agreement
with those reported for penciclovir.[3a,b] This clearly indicates a regio-
selective alkylation at the N9 position in 10 to yield the alkylated
purine 14 as a mixture of cis and trans isomers. The regioselectivity
displayed by 13 also suggests that, in addition to the steric effect as
proposed by Geen et al.,[3e] the ꢁ–ꢁ electronic interaction between
the benzylidene phenyl and purine base groups might synergistically
contribute to maximize the N9-alkylation of 9. The exact origin of this
high regioselectivity needs further investigation.
EXPERIMENTAL
General Methods
Melting points were measured on an Electrothermal Digital Melting
1
Point Apparatus IA9300 and are uncorrected. H NMR spectra were
recorded on a Brucker AM360 in D2O, CDCl3, or in DMSO-d6 with
acetone (ꢀ 2.22 for D2O) and TMS (for CDCl3 and DMSO-d6) as internal
standards. High-resolution mass spectra (HRMS) were obtained using a
positive mode on a VG 70VSE (AutoSpec) for EI and on a VG ZAB-SE
for FAB. Ultra violet spectra were recorded on a Beckman DU-600
spectrophotometer. TLC was performed on precoated POLYGRAMÕ
SIL G/UV254 plates. The silica gel used for an open column chromato-
graphy was EM Science Silica Gel 40 (0.063–0.200 mm). The starting
materials triethyl 1,1,2-ethanetricarboxylate (2) and 2-amino-6-chloro-
purine (9), as well as all other reagents and anhydrous solvents, were
purchased from Aldrich Chemical Co.
2-Hydroxymethyl-1,4-butanediol[3a,b] (3)
The reaction was carried out using
a modification of a
procedure previously reported.[3a,b] To a refluxing solution of triethyl

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3902
Toyokuni et al.
1,1,2-ethanetricarboxylate (2) (46 mL, 0.2 mol) and NaBH4 (20 g) in
t-BuOH (400 mL) was added MeOH (25 mL) in portions over a period
of 30 min. Reflux was continued for an additional 30 min, the mixture
was cooled and neutralized with 3 M HCl (ꢀ65 mL). The resulting
precipitate was removed by filtration and the filtrate was evaporated.
The residue was dissolved in a minimum amount of H2O (the solution
should not be viscous) and passed successively through anion-exchange
resign (Amberlite IRA-400 OHꢁ; 0.018–0.045 mesh; 30 ꢂ 380 mm) and
cation-exchange resin (Amberlite IR-120 Hþ; 0.014–0.040 mesh;
30 ꢂ 380 mm) column chromatography with H2O as eluent. The
vanillin-stain positive fractions were combined and evaporated to give
3 (19 g, 79%) as a clear viscous oil: 1H NMR (D2O) ꢀ 1.55 (pseudo q, 2H,
J ¼ 7 Hz, H-3), 1.76 (pseudo septet, 1H, J ¼ 7 Hz, H-2), 3.58 (d, 4H,
1
J ¼ 7 Hz, H-1), 3.65 (t, 2H, J ¼ 7 Hz, H-4). The H NMR spectrum was
in good agreement with the reported data.[3b]
2-(2-Phenyl-1,3-dioxane-5-yl)ethanol[8] (12)
A solution of 3 (18 g, 0.15 mol) in anhydrous THF (500 mL) was
treated with benzaldehyde dimethyl acetal (30 mL, 0.2 mol) in the
presence of TsOH monohydrate (3 mg, 15.5 mmol) at room temperature
for 1 h. The reaction mixture was poured onto saturated aq NaHCO3
(150 mL) and extracted with Et2O. The combined organic extracts were
dried over anhydrous MgSO4 and evaporated to give 12 (26 g, 83%) as a
1
colorless solid. The H NMR spectrum indicated that this was a mixture
of cis and trans isomers in an approximately 1:3 ratio. For the cis isomer:
1H NMR (CDCl3) ꢀ 1.55 (br s, 1H, H-5), 2.07 (pseudo q, 2H, J ¼ 7 Hz,
CH2CH2OH), 3.83 (pseudo t, 2H, J ¼ 7 Hz, CH2CH2OH), 4.12 (br d, 2H,
J ¼ 11 Hz), and 4.17 (br d, 2H, J ¼ 11 Hz) (H-4 and H-6), 4.86 (br s, 1H,
OH), 5.52 (s, 1H, H-2), 7.3–7.7 (m, 5H, Ar H); for the trans isomer:
1H NMR (CDCl3) ꢀ 1.35 (pseudo q, 2H, J ¼ 5 Hz, CH2CH2OH), 2.29
(m, 1H, H-5), 3.59 (pseudo t, 2H, J ¼ 11 Hz, H-4ax and H-6ax), 3.66
(pseudo t, 2H, J ¼ 7 Hz, CH2CH2OH), 4.27 (dd, 2H, J ¼ 11 and 4 Hz,
H-4eq and H-6eq), 4.86 (br s, 1H, OH), 5.43 (s, 1H, H-2), 7.3–7.7 (m, 5H,
Ar H). HREIMS: calcd. for C12H16O3 208.1099. Found: 208.1097.
5-(2-Bromoethyl)-2-phenyl-1,3-dioxane (13)
To an ice-cooled solution of 12 (5.0 g, 24 mmol) and CBr4 (12.6 g,
37.6 mmol) in anhydrous CH2Cl2 (100 mL) was added Ph3P

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of Penciclovir
3903
(10.0 g, 37.7 mmol) in portions over a period of 10 min with vigorous
stirring. Stirring was continued in an ice-bath for 1.5 h, the reaction
mixture was diluted with CH2Cl2 (200 mL) and washed with saturated
aq NaHCO3 (2 ꢂ 200 mL). The organic layer was dried over anhydrous
MgSO4 and evaporated to yield a light yellow oil. The crude product was
purified by silica-gel column chromatography with hexane–acetone (3:1,
1
v/v) to give 13 (5.3 g, 81%) as a pale yellow oil. The H NMR spectrum
indicated that this was a mixture of cis and trans isomers in an approxi-
mately 1:1.5 ratio. For the cis isomer: 1H NMR (CDCl3) ꢀ 1.80 (br s, 1H,
H-5), 2.40 (pseudo q, 2H, J ¼ 7 Hz, CH2CH2Br), 3.60 (pseudo t, 2H,
J ¼ 7 Hz, CH2CH2Br), 4.07 (br d, 2H, J ¼ 11 Hz), and 4.15 (br d, 2H,
J ¼ 11 Hz) (H-4 and H-6), 5.51 (s, 1H, H-2), 7.3–7.5 (m, 5H, Ar H); for
the trans isomer: 1H NMR (CDCl3) ꢀ 1.71 (pseudo q, 2H, J ¼ 7 Hz,
CH2CH2Br), 2.37 (m, 1H, H-5), 3.39 (pseudo t, 2H, J ¼ 7 Hz,
CH2CH2Br), 3.59 (pseudo t, 2H, J ¼ 11 Hz, H-4ax and H-6ax), 4.27
(dd, 2H, J ¼ 11 and 5 Hz, H-4eq and H-6eq), 5.42 (s, 1H, H-2), 7.3–7.5
(m, 5H, Ar H). Without further characterization the product 13 was used
in the next step the same day (see below).
2-Amino-6-chloro-9-[2-(2-phenyl-1,3-dioxane-5-yl)-
ethyl]guanine (14)
A mixture of 13 (4.0 g, 14.8 mmol), 2-amino-6-chloropurine (9) (2.8 g,
16.3 mmol) and K2CO3 (3.4 g, 24.6 mmol) in anhydrous DMF (50 mL)
was stirred at room temperature for 3 d. The brown colored reaction
mixture was then filtered and the filtrate was evaporated to give a dark
orange oil. The crude product was placed on a silica-gel column and
eluted first with CHCl3–MeOH (80:1, v/v) to remove less polar impurities
and then with CHCl3–MeOH (60:1, v/v) to give 14 (5.0 g, 94% based on
1
13). The H NMR spectrum indicated that this was a mixture of cis and
trans isomers in an approximately 1:1.5 ratio. For the cis isomer:
1H NMR (CDCl3) ꢀ 1.43 (br s, 1H, H-50), 2.42 (pseudo q, 2H, J ¼ 7 Hz,
CH2CH2N), 4.12 (t, 2H, J ¼ 7 Hz, CH2CH2N), 4.15 (br s, 4H, H-40 and
H-60), 5.13 (br s, 2H, NH2), 5.53 (s, 1H, H-20), 7.3–7.5 (m, 5H, Ar H),
1
7.80 (s, 1H, H-8); for the trans isomer: H NMR (CDCl3) ꢀ 1.71 (pseudo
q, 2H, J ¼ 7 Hz, CH2CH2N), 2.18 (m, 1H, H-50), 3.63 (pseudo t,
2H, J ¼ 11 Hz, H-40ax and H-60ax), 4.12 (t, 2H, J ¼ 7 Hz, CH2CH2N),
4.30 (dd, 2H, J ¼ 11 and 5 Hz, H-40eq and H-60eq), 5.13 (br s, 2H,
NH2), 5.44 (s, 1H, H-20), 7.3–7.5 (m, 5H, Ar H), 7.77 (s, 1H, H-8).
HRFABMS: calcd. for C17H19ClN5O2 (M þ H) 360.1227. Found:
360.1216.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3904
Toyokuni et al.
9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine
(Penciclovir)[3a,b] (1)
A solution of 14 (4.7 g, 13.4 mmol) in 2 M HCl (15 mL) was heated to
90ꢃC for 3 h. The reaction mixture was cooled to room temperature and
neutralized with 10% aq NaOH. The mixture was placed in a refrigerator
for 2 d and the resulting precipitate was collected by filtration to yield 1
(2.8 g, 83%) as a colorless crystalline solid: m.p. 268.4–269.2ꢃC [Lit.[3a,b]
275–277ꢃC]. UV (H2O) ꢂmax 252 and 273 (sh) nm [Lit[3a,b] 253 and 270
(sh) nm]. 1H NMR (DMSO-d6) ꢀ 1.42 (pseudo septet, 1H, J ¼ 7 Hz, H-30),
1.69 (pseudo q, 2H, J ¼ 7 Hz, H-20), 3.37 (ddd, 2H, J ¼ 11, 7 and 7 Hz)
and 3.41 (ddd, 2H, J ¼ 11, 7 and 7 Hz) (CH2OH), 3.98 (t, 2H, J ¼ 7 Hz,
H-10), 4.42 (t, 2H, J ¼ 7 Hz, OH), 6.42 (br s, 2H, NH2), 7.67 (s, 1H, H-8),
1
10.50 (br s, 1H, H-1). The H NMR spectrum is in good agreement with
the literature data.[3a,b]
ACKNOWLEDGMENTS
This work was supported by the Department of Energy grant
DE-FC03-87ER60615.
REFERENCES
1. Snoeck, R. Int. J. Antimicrob. Agents 2000, 16, 157–159.
2. Pandit, U.K.; Grose, W.F.A.; Eggelte, T.A. Synth. Commun. 1972,
2, 345–351.
3. Some examples include: (a) Harnden, M.R.; Jarvest, R.L.
Tetrahedron Lett. 1985, 26, 4265–4268; (b) Harnden, M.R.;
Jarvest, R.L.; Bacon, T.H.; Boyd, M.R. J. Med. Chem. 1987, 30,
1636–1642; (c) Tippie, M.A.; Martin, J.C.; Smee, D.F.; Matthews,
T.R.; Verheyden, J.P.H. Nucleosides Nucleotides 1984, 3, 525–535;
(d) Hannah, J.; Tolman, R.L.; Karkas, J.D.; Liou, R.; Perry, H.C.;
Field, A.K. J. Heterocyclic Chem. 1989, 26, 1261–1271; (e)
Choudary, B.M.; Geen, G.R.; Grinter, T.J.; MacBeath, F.S.;
Parratt, M.J. Nucleosides Nucleotides 1994, 13, 979–996; (f)
Choudary, B.M.; Geen, G.R.; Kincey, P.M.; Parratt, M.J.; Dales,
J.R.M.; Johnson, G.P.; O’Donnell, S.; Tudor, D.W.; Woods, N.
Nucleosides Nucleotides 1996, 15, 981–994; (g) Brand, B.; Reese,
C.B.; Song, Q.; Visintin, C. Tetrahedron 1999, 55, 5239–5252; (h)
Geen, G.R.; Kincey, P.M.; Spoors, P.G. Tetrahedron Lett. 2001,
42, 1781–1784.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of Penciclovir
3905
4. For example see: (a) Gambhir, S.S.; Herschman, H.R.; Cherry, S.R.;
Barrio, J.R.; Satyamurthy, N.; Toyokuni, T.; Phelps, M.E.; Larson,
S.M.; Balatoni, J.; Finn, R.; Sadelain, M.; Tjuvajev, J.; Blasberg, R.
Neoplasia 2000, 2, 118–138; (b) Namavari, M.; Barrio, J.R.;
Toyokuni, T.; Gambhir, S.S.; Cherry, S.R.; Herschman, H.R.;
Phelps, M.E.; Satyamurthy. N. Nucl. Med. Biol. 2000, 27,
157–162; (c) Yaghoubi, S.; Barrio, J.R.; Dahlbom, M.; Iyer, M.;
Namavari, M.; Satyamurthy, N.; Goldman, R.; Herschman, H.R.;
Phelps, M.E.; Gambhir, S.S. J. Nucl. Med. 2001, 42, 1225–1234.
5. Soai, K.; Oyamada, H.; Ookawa, A. Synth. Commun. 1982, 12,
463–467.
6. Removal of borate by an anion-exchange resin has been reported.
See: Ikai, K.; Mikami, M.; Furukawa, Y.; Ho, S. WO Patent
9,944,976, Sep. 10, 1999.
7. For example see: (a) Greene, T.W.; Wuts, P.G.M. Protective Groups
in Organic Synthesis, 3rd Ed.; John Wiley & Sons, Inc.: New York,
1999; 217–224; (b) Collins, P.; Ferrier, R. Monosaccharides: Their
Chemistry and Their Roles in Natural Products; John Wiley & Sons,
Inc.: New York, 1995; 389–406.
8. The compound 12 was previously prepared by the reaction of 3 with
benzaldehyde in the presence of TsOH via constant removal of
water by azeotropic distillation with toluene at 80ꢃC. See:
Hamazaki, T.; Agehara, K.; Onishi, T.; Iwasaki, H. JP Patent
11,158,174, June 15, 1999.
9. A similar isomerization was reported during the transformation of 7
to 8 through the corresponding mesylate (see Ref. 3e).
10. We have been carrying out this coupling reaction during a weekend.
Harnden et al. reported that 6 and 9 were reacted at 4ꢃC overnight,
while Geen et al. left the mixture of 8 and 9 at room temperature for
18 h (see Ref. 3b and Ref. 3e, respectively).
11. Kjellberg, J.; Johansson, N.G. Tetrahedron 1986, 42, 6541–6544.
Received in the USA May 1, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.