Stereoselective N-Acylation Reactions of α-Alkoxy Carbamates

Full text of DOI:10.1021/jo980024c

2062
J . Org. Chem. 1998, 63, 2062-2063
The chemistry of the intermediate R-alkoxy carbamate
anion 4a is central to the origin of stereoselectivity of this
process. If anions such as 4a are configurationally stable,
then the acylations should proceed with complete preserva-
tion of the C(10) stereochemistry of the starting material.
On the other hand, if the carbamate anion is not stable with
respect to reversible elimination of the R-alkoxy substituent
(via the highly electrophilic N-carbamoylimine intermediate
5),17 then the C(10) stereochemistry in the reaction product
will be determined by the relative stabilities of the epimeric
R-alkoxy carbamate anions 4a and 4b and/or the rates of
their acylation and equilibration. Under these circum-
stances, one would anticipate generating comparable product
mixtures starting from either R-alkoxy carbamate diaste-
reomer. We report herein the results of several experiments
designed to address these issues, as well as define more
broadly the scope of these reactions.
Ster eoselective N-Acyla tion Rea ction s of
r-Alk oxy Ca r ba m a tes
William R. Roush*,1 and Lance A. Pfeifer
Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, and Department of Chemistry,
University of Michigan, Ann Arbor, Michigan 48109
Received J anuary 7, 1998
In connection with studies on the synthesis of mycala-
mides A and B,2,3 we reported that the base-promoted
N-acylation of carbamate 1 (Teoc ) CO2CH2CH2SiMe3) with
benzoyl chloride followed by deprotection of the Teoc unit
provided amide 2 with complete control of the C(10) stereo-
center.4 The excellent stereocontrol realized in this reaction
is striking, especially in view of Kishi’s report that the
corresponding amine, 3, is configurationally unstable under
acidic, neutral, and weakly basic conditions and that acyla-
tions of 3 with a pederic acid derivative provided a mixture
of C(10)-epimers.5 Although N-acylations and N-alkylations
of amides and carbamates are well-established transform-
ations,6-8 relatively few examples of these reactions with
R-alkoxy amides or carbamates are known,9-16 and the vast
majority of these shed no light on the stereoselectivity of
the base-promoted acylations of R-alkoxy carbamates such
as 1.
R-Methoxy carbamate 8 was prepared by O-methylation
of diol 6,18 ester hydrolysis, and then Curtius reaction of 7
in the presence of 2-(trimethylsilyl)ethanol.19 Treatment of
a THF solution of 8 with lithium hexamethyldisilazide
(LHMDS, 1.15 equiv) at -78 °C for 30 min followed by
addition of benzoyl chloride (1.5 equiv) provided imide 9a
as a single diastereomer in 84% yield. When the carbamate
anion solution was allowed to warm to 0 °C before addition
of benzoyl chloride, imide 9a was again obtained as a single
diastereomer, albeit in lower yield (48%). Similarly, acyla-
tion of 8 by using in situ generated20 C6H11COCl or the
mixed anhydride 11a in the presence of DMAP (1 equiv)
provided imide 9b in 75-78% yield. However, when mixed
anhydride 11b was utilized, substantial quantities of 12
were obtained (20-37%) in addition to 9b (43-47%).
Deprotection of 9a or 9b by treatment with n-Bu4NF in
THF or DMF at 0 °C provided amides 10a and 10b in 90-
92% yield. In each case, the product was a single diastere-
1
omer according to H NMR analysis. The stereochemistry
of 10a was verified by a single-crystal X-ray analysis,21
which established that this two-step acylation-deprotection
sequence proceeded with retention of stereochemistry of the
R-methoxy carbamate center.
Additional studies of the R-alkoxy carbamate acylation
protocol were performed by using the N-glycosyl carbamates
14 and 15, which were prepared by acylation of glucosyl-
amine 1322 with Teoc-Cl.23 This sequence provided a 4:1
mixture of 14 and 15, which were separated chromatographi-
cally. Acylation of the anion of 14 in THF at -78 °C with
several freshly distilled acid chlorides (e.g., C6H5COCl,
(1) Correspondence to this author should be sent to the University of
Michigan address.
(2) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Thompson, A. M. J . Org.
Chem. 1990, 55, 223.
(3) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Pannell, L. K. J . Am.
Chem. Soc. 1988, 110, 4850.
(15) Hioki, H.; Okuda, M.; Miyagi, W.; Ito, S. Tetrahedron Lett. 1993,
34, 6131.
(16) Hansen, M. M.; Harkness, A. R.; Coffey, D. S.; Bordwell, F. G.; Zhao,
Y. Tetrahedron Lett. 1995, 36, 8949.
(17) Malassa, I.; Matthies, D. Chemiker-Zeitung 1987, 111, 181.
(18) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768.
(19) Shiori, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972, 94,
6203.
(20) Mixed anhydrides 11a , 11b, and C6H11COCl were generated in situ
by treatment of C6H11CO2H (1 equiv) with n-BuLi (1.1 equiv) in THF at
-78 °C in the presence of activated 4 Å molecular sieves (20 mg/mL of THF).
This solution was warmed to 0 °C and then was treated with 1.0 equiv of
Ph2POCl, C6H2Cl3COCl, or (COCl)2 for 1 h at 23 °C. DMAP (1 equiv) was
added, and then this solution was transferred by syringe to the -78 °C
solution of the carbamate anion.
(21) Details of the X-ray strcture analysis of 10a are provided in Report
No. 96197 of the Indiana University Molecular Structure Center. Final
residuals are R(F) ) 0.0296 and Rw(F) ) 0.0307. We thank Dr. Kirsten
Folting for performing this analysis.
(4) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
(5) Hong, C. Y.; Kishi, Y. J . Org. Chem. 1990, 55, 4242.
(6) For a general review of amide and carbamate acylations, see: Challis,
J . In The Chemistry of Amides; Zabicky, E., Ed.; Wiley: New York, 1970.
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2127.
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S0022-3263(98)00024-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/17/1998

Communications
J . Org. Chem., Vol. 63, No. 7, 1998 2063
MeO2CCOCl, MeCOCl, and PMBOCH2COCl) provided the
corresponding imides 16a -c and 16e in 70-84% yields as
single diastereomers. However, when PMBOCH2COCl was
generated in situ (by treatment of the corresponding car-
boxylic acid with 1.1 equiv of BuLi in THF followed by
(COCl)2), the yield of 16f was only 37%. On the other hand,
in situ generated20 mixed anhydrides 11a-c reacted smoothly
with the lithium anion of 14, providing imides 16d and 16f
in 79-83% yield. The reaction of dioxalanedione 11d 24 with
the lithium anion of 14 provided the cyclic imide 18 as the
major product (78%). Decarbamoylation of imides 16a -f
proceeded in excellent yield (88-96%), giving a single
diastereomer of 17 (the â-anomer) in all cases.
hydes gave extremely poor yields (e.g., 3% with 11a ),
suggesting that the hindered anion functions in these cases
as a base rather than as a nucleophile.
Acylations of the R-N-glucosyl carbamate 15 were much
less efficient, owing to the very hindered nature of the axial
carbamate anion. For example, acylation of the lithium
anion of 15 with benzoyl chloride required a reaction
temperature of 0 °C for product formation to occur. Under
these conditions, carbamate 19 was obtained in 61% yield,
along with recovered 15 (38%). Moreover, the deprotection
of 19 was very sluggish in THF and, therefore, was per-
formed with TBAF in DMF. This provided the R-N-gluco-
sylbenzamide 20 in 87% yield, along with 3% of the
corresponding â-anomer 17a . This is the only case where
we observed any epimerization of the R-alkoxy carbamate
stereocenter. Finally, attempted acylation of the lithium
anion of 15 with active ester derivatives of aliphatic alde-
In summary, these studies establish that R-alkoxy car-
bamate anions (e.g., 4a ) are configurationally stable ()97%)
under the conditions of these acylation reactions, unlike the
corresponding R-alkoxy amines. We anticipate that this
methodology will prove useful in the stereocontrolled syn-
thesis of the mycalamides as well as N-linked glycopeptides.
Ack n ow led gm en t. This research was supported by
grants from the National Institutes of Health (GM 38907
and RR 10537).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and full characterization data for all new compounds (20
pages).
(24) Toyooka, K.; Takeuchi, Y.; Kubota, S. Heterocycles 1989, 29, 975.
J O980024C